Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
This variantScenario
BenignPathogenic
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
About PALB2
PALB2 encodes a tumor suppressor protein that partners with BRCA2 (and also interacts with BRCA1) to repair double-stranded DNA breaks through the homologous recombination pathway. It acts as a scaffold that stabilizes BRCA2 in the cell nucleus and helps recruit DNA-repair machinery to sites of damage. Inherited mutations in PALB2 increase susceptibility to breast cancer, with smaller associated risks for ovarian, pancreatic, and prostate cancer and melanoma, and inheriting two mutated copies causes Fanconi anemia complementation group N. Rare somatic alterations in PALB2 are also found across various tumor types.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen PALB2 VCEP v1.2. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at Very Strong: c.886del creates a premature stop p.(Met296Ter) in exon 4 of 13, upstream of p.Tyr1183 with predicted NMD, per the PALB2 VCEP PVS1 decision tree.
PM2Supporting
PM2 · supporting
Met (supporting): gnomAD v4.1 total AF of 0.000248% (4/1,613,998 alleles) falls below the PALB2 VCEP PM2 threshold of 1/300,000 (0.000333%).
PM5Supporting
PM5 · supporting
Met (supporting): frameshift c.886del creates a premature stop at codon 296, upstream of p.Tyr1183*, satisfying the PALB2 VCEP PM5_Supporting truncation-cutoff rule.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
Pathogenic: PVS1 (very strong) plus PM2 and PM5 (both supporting) satisfy Rule 4 of the ClinGen HBOC PALB2 expert panel specification.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
4 / 1,613,998 alleles
gnomAD v4.1: 4 / 1,613,998 alleles. Recorded AF 2.47832e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97855e-06; MAF= 0.00040%, 1/251348 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79709e-06; MAF= 0.00088%, 1/113674 alleles, homozygotes = 0).
ACMG/AMP criteria under ClinGen PALB2 VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 3 not met · 4 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 is met at Very Strong: NM_024675.4:c.886del creates an immediate premature termination codon p.(Met296Ter) in exon 4 of 13 of the canonical PALB2 transcript; the PTC is upstream of p.Tyr1183 and is predicted to undergo NMD (~2.5 kb upstream of the final exon-exon junction), and germline LoF is an established PALB2 disease mechanism per the ClinGen HBOC VCEP v1.2, whose PVS1 decision tree therefore assigns full PVS1 (Very Strong).
PM4 is not applicable because the PALB2 ClinGen VCEP v1.2 specification declares it 'Not Applicable' and the variant is a frameshift/truncating event rather than an in-frame protein-length change or stop-loss variant.
BP3 is not applicable because the PALB2 ClinGen VCEP v1.2 specification declares it 'Not Applicable' and the variant is a frameshift deletion rather than an in-frame indel in a repetitive region.
NM_024675.4:c.886del is a truncating frameshift (NP_078951.2:p.(Met296Ter)); within the codon-residue-domain group only PM5 is met, at supporting strength, under the PALB2 HBOP VCEP v1.2 truncation-cutoff rule because the premature termination codon at residue 296 lies upstream of the p.Tyr1183* boundary (the location of the most C-terminal known pathogenic PALB2 truncating variant).
PS1 is not applicable: the PALB2 VCEP confines PS1 to the PALB2 PS1 splicing table for splice variants and forbids use for non-splice classes; c.886del shows no predicted splice impact (SpliceAI max delta 0.018) and no alternate-nucleotide variant producing the same protein consequence exists.
PM1 and PP2 are not applicable because the PALB2 VCEP v1.2 declares both not usable (missense pathogenic mechanism not confirmed/refuted for PALB2) and provides no approved PALB2 critical-functional-domain table; the variant is additionally not a missense change.
BP1 is not applicable because the VCEP's supporting rule applies only to missense variants, whereas c.886del is a truncating loss-of-function allele.
The governing framework is the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification for PALB2 v1.2 (framework_mode=vcep, cspec), which applies in the autosomal dominant PALB2-related cancer predisposition context of this case.
PS2 and PM6 are framework-level exclusions: the VCEP marks both Not Applicable and instructs 'Do not use for AD or AR disease' (AD: informative de novo occurrences not yet observed and breast cancer is common/sporadic; AR: de novo too rare/informative phase essentially unconfirmable). Both are returned as not_applicable regardless of data, and no de novo or assumed-de-novo observation for c.886del exists in ClinVar VCV000143979 or the fetched literature.
PP1 and BS4 are both not_assessed because the VCEP mandates quantitative segregation analysis (LOD/LR thresholds) and this variant-centric case contains no proband pedigree, affected-relatives testing, or computed LOD/LR for c.886del. The only segregation-study paper that mentions the variant (PMID:25099575) lists c.886del among 48 pooled loss-of-function mutations without variant-specific segregation counts, and PMID:30089731 reports a single carrier with no family testing.
Absence of segregation data must not be misread as evidence of non-segregation: BS4 would require a computed LOD <= -0.32 (supporting) or lower, which no source provides.
The ClinGen HBOC EP PALB2 VCEP v1.2 specification (cspec doc 1526222356) is the governing framework and declares both PS3 and BS3 'Not applicable' for PALB2, with all strength partitions not applicable.
No validated variant-specific functional assay evidence for NM_024675.4:c.886del (p.Met296Ter) exists in either direction (damaging or non-damaging) in the retrieved literature: the seven full-text papers are case/cohort, segregation/risk, or review studies, none reporting an in vitro/in vivo assay of this variant.
PS3 and BS3 are therefore both recorded as not_applicable and contribute no pathogenic or benign weight to the classification; the truncating variant's presumed loss-of-function impact is addressed through the PALB2 PVS1 decision tree instead.
Framework note: the PS3/BS3 rows in the PALB2 v1.2 CSPEC carry shared-document 'instructionsToUse' text referencing ATM-specific protein assays and PVS1_O/BP7_O RNA codes, but the controlling applicability fields for PALB2 are 'Not applicable', so these rows do not authorize use of PS3/BS3 for PALB2.
Governing framework: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 specification v1.2 (cspec, doc 1526222356), applied in preference to generic ACMG/AMP.
PS4 is applicable (Strong tier only) but not assessed: the sole case-control study (PMID:28779002) reports PALB2 protein-truncating-variant class-level enrichment meeting the numeric gate (OR 4.69, 95% CI 2.27-9.68, p=6.9e-6; 6.9e-6 <= 0.05 yes, 4.69 >= 3 yes, 2.27 >= 1.5 yes) without enumerating c.886del, and PS4_Moderate proband counting is disallowed by the VCEP; attribution of class-level data to this exact variant requires expert-panel confirmation.
PP4, PP5, BP5 and BP6 are declared not applicable by the PALB2 VCEP v1.2; additionally, VCV000143979 has no exact-variant ClinVar expert-panel classification (2-star aggregate of ordinary laboratory submissions only), so PP5/BP6 could not be triggered under the group rule even under generic ACMG.
No allelic evidence is available for PALB2 c.886del p.(Met296Ter): the case evidence contains no proband-level genotype, zygosity, phase, or pedigree data.
PM3 is not assessed: the variant is not documented in trans with a second pathogenic PALB2 variant in any affected proband, and the two papers that report this exact variant (PMID:30089731, PMID:25099575) provide only a monoallelic carrier observation and a family-cohort listing, respectively, with no biallelic/phase content.
BP2 is not applicable under the governing PALB2 HBOP VCEP v1.2 specification, which sets BP2 applicability to 'Not Applicable'.
Population frequency (gnomAD v4.1 AF 2.48e-06, 0 homozygotes) satisfies the PM3 <=0.01% general-population gate, so any future PM3 application would hinge on obtaining trans-phase or biallelic case data, not on frequency.
All three criteria owned by this group (PP3, BP4, BP7) are not_applicable by scope, decided before any predictor score is considered.
NM_024675.4:c.886del is a single-nucleotide deletion in PALB2 exon 4 coding sequence that shifts the reading frame and creates an immediate premature termination codon, p.(Met296Ter) [also rendered p.(Lys295_Met296insTer) and p.M296X]; it is a protein-truncating (frameshift/nonsense) variant, not a missense, not a splice-region/intronic variant, and not a synonymous variant.
PP3 and BP4 are calibrated for missense impact or for splice-impact prediction in silent/missense-in-frame/intronic variants (PALB2 VCEP v1.2: SpliceAI >= 0.2 for PP3, <= 0.1 for BP4); the governing VCEP explicitly does not use missense predictors for PALB2 and never applies these codes to truncating variants, whose impact is assessed under PVS1. A retrieved SpliceAI result (max delta 0.018) was therefore consciously not evaluated.
BP7 is restricted by the PALB2 VCEP to synonymous and deep intronic variants, which this frameshift allele is not.
No BayesDel/REVEL/aGVGD or other missense in-silico scores were present in the case data, and none were required given the variant class.
All four population criteria were adjudicated under the ClinGen HBOP EP PALB2 VCEP specification v1.2 (cspec doc 1526222356); generic ACMG/AMP 2015 thresholds were not used because an applicable gene-specific specification exists.
The variant NM_024675.4:c.886del (p.Met296Ter) is ultra-rare in every population dataset: gnomAD v4.1 total AF 0.000248% (4/1,613,998 alleles), grpmax FAF 0.000079%, 0 homozygotes; gnomAD v2.1 1/251,348 alleles, 0 homozygotes; absent from gnomAD-Canada v1.0.
BA1 not met: grpmax FAF 0.000079% is >1,000-fold below the VCEP >0.1% stand-alone threshold. BS1 not met: grpmax FAF is ~127-fold below the VCEP >0.01% strong threshold.
BS2 not met: 0 points under the FA BS2 point tables because no homozygote or unaffected-carrier observation exists in any population dataset or the fetched literature.
PM2 met at supporting strength: gnomAD v4.1 frequency (total AF 0.000248%, grpmax FAF 0.000079%) is below the VCEP 1/300,000 (0.000333%) threshold; the marginal NFE 4-allele AF excess is a threshold artifact of sampling noise.
Population evidence therefore contributes no benign criteria (BA1/BS1/BS2 all not met) and one pathogenic supporting criterion (PM2_Supporting).
No criteria match.
Met · 3
PVS1Very strongMet at Very Strong: c.886del creates a premature stop p.(Met296Ter) in exon 4 of 13, upstream of p.Tyr1183 with predicted NMD, per the PALB2 VCEP PVS1 decision tree.
Details ▾Hide ▴
Reasoning
NM_024675.4:c.886del is a single-nucleotide deletion in exon 4 (cDNA 212-1684 of 13 exons; Mutalyzer selector data) that shifts the reading frame and produces an immediate premature termination codon at codon 296, p.(Met296Ter); the predicted translation product ends at residue 295 of the 1186-aa NP_078951.2 PALB2 protein, deleting the C-terminal ~75% including the WD40 beta-propeller domain that the ClinGen HBOC PALB2 VCEP v1.2 (cspec) considers indispensable. Germline LoF is an established PALB2 disease mechanism: the VCEP applies PVS1 via the PALB2 PVS1 Decision Tree (strengths Very Strong through Supporting), and its truncation boundary text puts frameshifting/truncating variants with premature termination codons upstream of p.Tyr1183 (the most C-terminal known truncating pathogenic variant) in PVS1 scope; the codon 296 PTC is far upstream of p.Tyr1183. The VCEP also notes that no alternate splice isoform is a candidate rescue transcript and that LoF variants are rare in gnomAD in all PALB2 exons. NMD is predicted: the PTC lies ~0.8 kb upstream of the exon 4/5 junction and ~2.5 kb upstream of the final exon-exon junction, i.e., not in the last exon and far beyond the ~50-55 nt NMD boundary, so per the ClinGen SVI PVS1 decision tree (PMC6185798, PMID 30192042) adopted by the VCEP an NMD-prone premature stop in a LoF-established gene warrants PVS1 at Very Strong. PMID:30089731 reports the identical variant (NM_024675:exon4:c.886delA, p.M296X) as a germline, Sanger-confirmed PALB2 truncating allele in a cancer-susceptibility cohort, confirming transcript/exon location and truncating consequence. PMID:25099575 lists c.886del (frameshift/deletion class) among 48 distinct PALB2 loss-of-function mutations in 154 breast-cancer families (Figure 1A), confirming it is a bona fide LoF allele. PMID:28779002 shows PALB2 protein-truncating variants as a class carry OR 4.69 (95% CI 2.27-9.68), with truncations outside the C-terminal 280 codons carrying the higher OR 5.79 (95% CI 2.10-16.0); the p.Met296Ter PTC is not in that lower-risk C-terminal zone, supporting no strength reduction for distal/partial-loss effects.
Rule
Use PALB2 PVS1 Decision Tree (ClinGen HBOC VCEP PALB2 v1.2)
Evidence considered
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 specification v1.2 (cspec): PVS1 is applied through the 'PALB2 PVS1 Decision Tree' with strengths Very Strong/Strong/Moderate/Supporting; truncation-boundary text applies to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183; the WD40 beta-propeller and coiled-coil domains are considered indispensable; no alternate splice isoform is a candidate rescue transcript; LoF variants are rare in gnomAD in all exons.
Mutalyzer normalization of NM_024675.4:c.886del predicts p.(Met296Ter): the translated ORF terminates at residue 295, a premature stop at codon 296 of NP_078951.2 (full-length 1186 aa); transcript selector data place the variant in exon 4 (cDNA positions 212-1684) of 13 exons, so the PTC is ~0.8 kb upstream of the exon 4/5 junction and ~2.5 kb upstream of the final exon-exon junction.
ClinGen SVI PVS1 recommendations (PMC6185798; PMID 30192042): for a null variant in a gene with established LoF mechanism, PVS1 (Very Strong) applies when the premature termination codon is predicted to undergo NMD, practically defined as a stop located more than 50-55 nt upstream of the final exon-exon junction; a PTC in exon 4 of 13 meets this.
PMID:30089731 reports the exact variant as a germline PALB2 truncating allele, 'NM_024675:exon4:c.886delA (p.M296X)', Sanger-confirmed in a 61-patient high-frequency basal cell carcinoma cohort (Table 2), confirming the variant's location in canonical-transcript exon 4 and its protein-truncating consequence.
PMID:25099575 lists c.886del among 48 different PALB2 loss-of-function mutations (frameshift/deletion class) identified in 154 families with 362 PALB2 LoF carriers (Figure 1A), confirming the allele is a bona fide LoF/truncating PALB2 variant used in breast-cancer risk analyses.
PMID:28779002: PALB2 protein-truncating variants as a class confer high breast-cancer risk (OR 4.69, 95% CI 2.27-9.68, p=6.9e-6), and truncations outside the final 280 codons carry OR 5.79 (95% CI 2.10-16.0) versus OR 3.57 for C-terminal truncations; the p.Met296Ter PTC is outside the lower-risk C-terminal region, supporting no distal-region downgrade.
Still missing
No RNA/NMD assay was available; NMD is predicted from the PTC position (>55 nt upstream of the final exon-exon junction) rather than experimentally confirmed. If RNA evidence later showed NMD escape, the decision tree would call for PVS1_Strong rather than PVS1_Very Strong.
The PALB2 PVS1 Decision Tree / Exon Map / PVS1 Guide attachments referenced by the VCEP were not separately retrievable in the case materials; the VCEP rule text plus the SVI PVS1 decision tree (PMC6185798) were applied.
PM2SupportingMet (supporting): gnomAD v4.1 total AF of 0.000248% (4/1,613,998 alleles) falls below the PALB2 VCEP PM2 threshold of 1/300,000 (0.000333%).
Details ▾Hide ▴
Reasoning
The PALB2 VCEP v1.2 PM2 rule (Supporting strength) is met when 'Frequency <= 1/300,000 (0.000333%) in gnomAD v4 dataset'. gnomAD v4.1 reports total AF = 2.478e-06 (0.000248%; 4/1,613,998 alleles; MAF 0.00025%) and joint grpmax filtering AF = 7.9e-07 (0.000079%), both at or below the 0.000333% (1/300,000) threshold, so PM2_Supporting is met. Rarity is corroborated by gnomAD v2.1 (1/251,348 alleles) and absence from gnomAD-Canada v1.0. Threshold-artifact note: the NFE subpopulation AF (3.39e-06 = 0.000339%) marginally exceeds 0.000333% on only 4 alleles among 1,179,946 NFE chromosomes; this single-4-allele fluctuation is sampling noise and does not undermine the rarity conclusion, which rests on the total AF and the grpmax filtering AF (the same gnomAD filtering metric the VCEP uses for BA1/BS1). No frequency-based benign or artifact caveat applies at these allele counts, and the variant is confirmed by Sanger sequencing in a clinical report (PMID:30089731).
Rule
Frequency <= 1/300,000 (0.000333%) in gnomAD v4 dataset (Supporting)
Evidence considered
PALB2 ClinGen HBOP VCEP v1.2 PM2 rule: Supporting when frequency <=1/300,000 (0.000333%) in the gnomAD v4 dataset (cspec).
gnomAD v4.1: total AF = 2.478e-06 (0.000248%, 4/1,613,998 alleles), grpmax FAF = 7.9e-07 (0.000079%) - both below the 0.000333% threshold.
gnomAD v4.1 NFE subpopulation AF = 3.39e-06 (0.000339%, 4/1,179,946 alleles) marginally exceeds 0.000333% on 4 alleles; treated as sampling noise given total AF and grpmax FAF both pass.
PM5SupportingMet (supporting): frameshift c.886del creates a premature stop at codon 296, upstream of p.Tyr1183*, satisfying the PALB2 VCEP PM5_Supporting truncation-cutoff rule.
Details ▾Hide ▴
Reasoning
The governing PALB2 HBOP VCEP specification v1.2 (cspec) declares PM5 'Applicable' and defines it as a truncation-cutoff rule rather than classic same-residue missense PM5: instructionsToUse 'Based on location of the most C-terminal known pathogenic variant, p.Tyr1183*. Use as PM5_Supporting (not moderate). Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2', with the single Supporting-strength rule 'Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183.' NM_024675.4:c.886del is a frameshifting deletion in exon 4 (reported as NM_024675:exon4:c.886delA, p.M296X, in PMID:30089731) that creates a premature termination codon at position 296 (NP_078951.2:p.(Met296Ter); ClinVar p.Lys295_Met296insTer). Codon 296 is upstream (N-terminal) of the p.Tyr1183* boundary - the location of the most C-terminal known pathogenic PALB2 truncating variant - so this allele falls inside the region in which PALB2 truncation is an established loss-of-function mechanism; the premature stop sits in exon 4 of 13, remote from the last exon-junction and expected to be NMD-prone, and it deletes all downstream functional elements including the WD40 beta-propeller. This PM5 application is the VCEP truncation-cutoff code (PM5_Supporting), not same-residue missense PM5: the PM5 comparator scan found 0 same-residue candidate variants and the VCEP expressly forbids PM5 for missense. Result: PM5 met at supporting strength.
Rule
PALB2 VCEP v1.2 PM5 (PM5_Supporting): apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183*; use as PM5_Supporting (not moderate); do not use for missense changes
Evidence considered
PALB2 HBOP VCEP v1.2 (cspec) PM5 card: 'Based on location of the most C-terminal known pathogenic variant, p.Tyr1183*. Use as PM5_Supporting (not moderate). Do not use for missense changes'; Supporting rule: 'Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183.'
c.886del is a frameshifting 1-bp deletion; its premature termination codon at position 296 (codon 296 < Tyr1183, i.e., upstream of the p.Tyr1183* cutoff) qualifies the allele for the PM5_Supporting truncation-cutoff rule.
PMID:30089731 documents the exact allele as NM_024675:exon4:c.886delA (p.M296X) in Table 2, confirming the frameshift/truncating class and exon-4 location used to place the premature stop well upstream of p.Tyr1183* and of the final exon.
PMID:25099575 lists c.886del among 48 different PALB2 loss-of-function (frameshift/deletion-class) mutations in 154 families (Figure 1A), confirming the allele is treated as a truncating loss-of-function PALB2 variant in a clinical family cohort.
The PM5 comparator scan (pm5_candidates) found 0 same-residue candidate variants and its mode note indicates PM5 here is the gene-specific truncation-cutoff framework rule, not classic same-residue missense PM5; consistent with the VCEP 'do not use for missense' instruction, no missense-comparator evidence is needed or used.
Still missing
NMD-proneness of the p.Met296Ter allele is inferred from its upstream exon-4 premature-stop position; no RNA/NMD functional assay data for this variant are present in the case evidence (the VCEP frameshift arm of the PM5 rule does not itself require RNA data).
BA1Not met: gnomAD v4.1 grpmax filtering AF of 0.000079% is over 1,000-fold below the PALB2 VCEP BA1 threshold of >0.1%.
Details ▾Hide ▴
Reasoning
Governing framework is the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP) EP PALB2 VCEP specification v1.2 (cspec doc 1526222356), which sets BA1 (Benign Stand Alone) at 'Grpmax Filtering AF >0.1% in gnomAD v4 dataset'. gnomAD v4.1 (joint) reports grpmax filtering AF = 7.9e-07 (0.000079%) for 16-23635659-AT-A, i.e. >1,000-fold below the 0.1% (1e-3) threshold; total AF is 2.478e-06 (4/1,613,998 alleles, MAF 0.00025%) and the highest population AF is NFE 3.39e-06 (4/1,179,946 alleles), both also far below 0.1%. gnomAD v2.1 corroborates extreme rarity (1/251,348 alleles). No population dataset approaches the stand-alone benign frequency threshold, so BA1 is not met.
Rule
Grpmax Filtering AF >.1% in gnomAD v4 dataset (Benign Stand Alone)
Evidence considered
PALB2 ClinGen HBOP VCEP v1.2 BA1 rule: stand-alone requires grpmax filtering AF >0.1% in the gnomAD v4 dataset (cspec).
gnomAD v4.1 joint grpmax FAF = 7.9e-07 (0.000079%), ~1,266-fold below the 0.1% BA1 threshold; total AF = 2.478e-06 (4/1,613,998 alleles; MAF 0.00025%); highest population AF NFE = 3.39e-06.
gnomAD v2.1 also shows only 1/251,348 alleles (total AF 3.98e-06), confirming the variant is not common in any large population dataset.
BS1Not met: gnomAD v4.1 grpmax filtering AF of 0.000079% is ~127-fold below the PALB2 VCEP BS1 threshold of >0.01%.
Details ▾Hide ▴
Reasoning
Under the governing ClinGen HBOP EP PALB2 VCEP v1.2 framework, BS1 (Benign Strong) requires 'Grpmax Filtering AF >0.01% in gnomAD v4 dataset'. gnomAD v4.1 grpmax filtering AF = 7.9e-07 (0.000079%), approximately 127-fold below the 0.01% (1e-4) BS1 threshold. The total AF (2.478e-06; 4/1,613,998 alleles) and the highest population AF (NFE 3.39e-06) likewise fall well below 0.01%. gnomAD v2.1 (1/251,348 alleles) is consistent. Because the variant is far too rare to support a benign strong population-frequency assertion, BS1 is not met.
Rule
Grpmax Filtering AF >.01% in gnomAD v4 dataset (Benign Strong)
Evidence considered
PALB2 ClinGen HBOP VCEP v1.2 BS1 rule: strong requires grpmax filtering AF >0.01% in the gnomAD v4 dataset (cspec).
gnomAD v4.1 joint grpmax FAF = 7.9e-07 (0.000079%), ~127-fold below the 0.01% BS1 threshold; total AF = 2.478e-06 (0.000248%), highest population AF NFE = 3.39e-06 (0.000339%).
gnomAD v2.1 corroborates rarity (1/251,348 alleles); no dataset shows the variant near the 0.01% carrier-frequency range.
BS2Not met: gnomAD v4.1 and v2.1 report zero homozygotes (0/1,613,998 and 0/251,348 alleles) and no unaffected-carrier observations, scoring 0 BS2 points.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP v1.2 assigns BS2 via the Fanconi Anemia BS2 point tables (points per proband): >=4 points = Strong, 2 points = Moderate, 1 point = Supporting; points accrue only from observations of the variant in unaffected individuals/population datasets (e.g., homozygotes or biallelic carriers without the expected phenotype). For NM_024675.4:c.886del there are no such observations: gnomAD v4.1 reports 0 homozygotes among 1,613,998 alleles and gnomAD v2.1 reports 0 homozygotes among 251,348 alleles, the variant is absent from gnomAD-Canada v1.0, and none of the fetched literature reports the variant in healthy or biallelic carriers (the single variant-specific report, PMID:30089731, is an affected proband in a high-frequency BCC cohort). Total BS2 points = 0, below even the 1-point supporting tier, so BS2 is not met. Homozygosity would in any case not be expected for PALB2 given that biallelic loss-of-function causes Fanconi anemia (FA-N), so absence of homozygotes alone is not treated as positive evidence.
Rule
BS2 >=4 points = Strong; BS2_Moderate = 2 points; BS2_Supporting = 1 point (Fanconi Anemia BS2 tables, points per proband)
gnomAD v4.1: 0 homozygotes in 1,613,998 alleles (total_hom 0; all population subgroups 0).
gnomAD v2.1: 0 homozygotes in 251,348 alleles (total_hom 0; all population subgroups 0).
gnomAD-Canada v1.0: variant absent.
No qualifying unaffected-individual observation for c.886del exists in any evidence source, so 0 BS2 points; the only variant-specific literature report (PMID:30089731) is an affected proband, which cannot contribute BS2 points.
Still missing
No large unaffected-elderly or population case-control dataset in the source registry reports this exact variant in healthy carriers; 0 homozygotes across gnomAD v2.1/v4.1 and absence from gnomAD-Canada are sufficient to conclude not met at any strength.
PS4Not assessed: no case-control study reports c.886del individually; PALB2 truncating-variant class-level OR 4.69 (p=6.9e-6) cannot be attributed to this exact variant.
Details ▾Hide ▴
Reasoning
Governing framework is the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer EP PALB2 specification v1.2 (cspec). Its PS4 rule, literally written for the Strong tier (the only usable tier; PS4_Moderate proband counting is explicitly 'Do not use'), states: 'Case-control studies; p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=3 OR lower 95% CI >=1.5).' Operator directions for this criterion: p-value strengthens as it goes DOWN (must be <=0.05), while OR/HR/RR and the lower 95% CI strengthen as they go UP (OR/HR/RR >=3, or lower 95% CI >=1.5). The only case-control study available, PMID:28779002 (Decker et al. 2017; 13,087 breast cancer cases vs 5,488 controls), reports enrichment for PALB2 protein-truncating variants as a CLASS: OR 4.69, 95% CI 2.27-9.68, p=6.9e-6. Substituted inequality check on class-level values: 6.9e-6 <= 0.05? yes; 4.69 >= 3? yes; lower 95% CI 2.27 >= 1.5? yes. However, c.886del (p.Met296Ter) is not individually enumerated anywhere in PMID:28779002 (variant_mentioned=false), so this exact variant's inclusion in, and contribution to, the class-level estimate cannot be confirmed, and the VCEP rule text contains no authorization to assign class-level PTV case-control enrichment to a specific unlisted truncating variant. PMID:25099575 lists c.886del in Figure 1A among 48 PALB2 loss-of-function mutations but provides no per-variant count and is a family-based (not case-control) risk analysis; PMID:30089731 reports a single c.886delA (p.M296X) carrier among 61 frequent-BCC patients with no control group (case observation only, and proband counting for PS4_Moderate is disallowed by this VCEP). Because no variant-specific case-control enrichment evidence is available, PS4 cannot be concluded met; it is recorded as not assessed pending expert-panel review of whether class-level PTV enrichment may be attributed to this exact truncating variant.
Rule
PALB2 VCEP v1.2 PS4 Strong: 'Case-control studies; p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=3 OR lower 95% CI >=1.5).' PS4_Moderate (proband counting) explicitly not used.
Evidence considered
PALB2 VCEP v1.2 (cspec) PS4 Strong rule text: 'Case-control studies; p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=3 OR lower 95% CI >=1.5).' Written with substituted class-level values: 6.9e-6 <= 0.05? yes; 4.69 >= 3? yes; 2.27 >= 1.5? yes.
PALB2 VCEP v1.2 PS4_Moderate is not usable ('Do not use. Proband counting for genes causing a common disorder need to be calibrated in a population-specific way before use'), so generic ACMG Note-2 case-observation counting cannot substitute for the case-control rule.
PMID:28779002 (Decker et al. 2017): population-based case-control, 13,087 breast cancer cases and 5,488 controls; PALB2 protein-truncating variants as a class had OR 4.69 (95% CI 2.27-9.68), p=6.9e-6, but c.886del is not individually reported, so the class estimate cannot be confirmed to include this exact variant.
PMID:25099575 (Antoniou et al. 2014): c.886del appears in Figure 1A among the 48 different PALB2 loss-of-function mutations across 154 families, without a per-variant family count; the reported breast-cancer risks are pooled, family-based estimates, not a case-control enrichment statistic for this variant.
PMID:30089731 (Cho et al. 2018): one carrier of NM_024675:exon4:c.886delA (p.M296X) listed in Table 2 of a 61-patient high-frequency BCC cohort; no control group and no enrichment statistic, so it cannot meet the PS4 case-control rule.
Other fetched full texts (PMID:18053174, PMID:25529982, PMID:28279176, PMID:28858227) do not report c.886del and contain no variant-specific case-control data.
Still missing
No case-control study reporting PALB2 c.886del individually (affected vs control counts with OR/HR/RR, p-value, and confidence interval) is available; only class-level protein-truncating-variant enrichment exists (PMID:28779002).
Full PALB2 VCEP v1.2 / ENIGMA documentation was not available in this case to confirm whether class-level PTV case-control enrichment may be attributed to individual truncating variants for PS4; expert-panel confirmation needed.
PM3Not assessed: no affected proband is documented with c.886del in trans with a second PALB2 pathogenic variant, and no phase or Fanconi-phenotype data exists.
Details ▾Hide ▴
Reasoning
Governing framework is the ClinGen HBOP VCEP PALB2 specification v1.2 (cspec), which declares PM3 applicable and scores it with the Fanconi Anemia per-proband point tables (PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong = >=4 points, PM3_VeryStrong = >=8 points); its original ACMG note states the criterion applies to recessive disorders where the variant is 'detected in trans with a pathogenic variant' and that phase must be determined by testing parents or offspring. PALB2 biallelic loss-of-function causes Fanconi anemia subtype FA-N, so an in-trans observation must occur in an affected proband with an FA-consistent phenotype or documented biallelic genotypes. No proband, pedigree, zygosity, or phase information exists anywhere in the case evidence, and no source reports c.886del in trans with a second pathogenic PALB2 variant. The only case-level sources that mention this exact variant were reviewed: PMID:30089731 reports a single germline monoallelic carrier (p.M296X) in a high-frequency BCC cohort with no second PALB2 allele, FA phenotype, or breakage testing; PMID:25099575 lists c.886del among 48 PALB2 loss-of-function mutations contributing to a 154-family segregation analysis (single family) but provides no variant-specific genotype-phase data. Neither yields an in-trans observation. The PM3 general-population gate (variant frequency <=0.01%) is satisfied (gnomAD v4.1 AF 2.48e-06, 4/1,613,998 alleles, 0 homozygotes), so frequency does not block PM3; the criterion is unassessable solely because no affected-proband trans-phase observation is documented. Result: not assessed, pending case-level or biallelic data.
Evidence considered
PALB2 HBOP VCEP v1.2 (cspec) PM3 rule: applicable, scored via Fanconi Anemia per-proband tables (PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong = >=4 points, PM3_VeryStrong = >=8 points); original ACMG note: 'For recessive disorders, detected in trans with a pathogenic variant. Note: This requires testing of parents (or offspring) to determine phase.'
No proband is described in the case evidence, so no genotype, zygosity, or phase information exists for this variant; an in-trans observation with a second pathogenic PALB2 allele cannot be established.
PMID:30089731, the only paper reporting this exact variant in a subject, describes a single germline monoallelic carrier (p.M296X, c.886delA) in a 61-patient high-frequency BCC cohort; no second PALB2 allele, FA phenotype, or chromosome-breakage testing is reported, so it provides no PM3 in-trans evidence.
PMID:25099575 includes c.886del among 48 different PALB2 loss-of-function mutations in a 154-family/362-member segregation cohort (variant present in a single family per Figure 1A) but reports no variant-specific genotype-phase or biallelic data, so it provides no PM3 in-trans evidence.
PM3 general consideration (variant population frequency must not exceed 0.01%) is met: gnomAD v4.1 AF 2.48e-06 (4/1,613,998 alleles, grpmax FAF 7.9e-07, 0 homozygotes); the missing element is the affected-proband trans-phase observation itself.
Still missing
No proband-level genotype, zygosity, or phase data (parental/offspring testing) for c.886del anywhere in the case evidence
No observation of c.886del in trans with a second pathogenic PALB2 variant in an affected proband (FA-N/biallelic context)
No Fanconi anemia phenotype or chromosomal breakage (DEB/MMC) study data available for any carrier
PP1Not assessed: no segregation or LOD data for c.886del; the PALB2 specification requires LOD >=0.3 or Bayes factor >=2:1 for supporting PP1.
Details ▾Hide ▴
Reasoning
Under the PALB2 CSPEC v1.2, PP1 for the autosomal dominant condition (PALB2-related cancer predisposition - the relevant context here, given the ClinVar condition "Familial cancer of breast") requires quantitative co-segregation: Supporting LOD >=0.3 or Bayes factor (LR) >=2:1, Moderate LOD >=0.60 or LR >=4:1, Strong LOD >=1.26 or LR >=18:1, computed by a method such as COOL Full-Likelihood Bayes. This variant-centric case carries no proband pedigree, affected-relatives testing, or computed LOD/LR, so no segregation evidence can be scored. The one directly relevant paper, PMID:25099575 (Antoniou et al. 2014, the 154-family PALB2 loss-of-function segregation/risk study), explicitly lists c.886del in Figure 1A but gives no variant-specific family segregation counts or LOD for it (it appears in a single family and the published risk/segregation estimates are pooled across all 48 loss-of-function mutations), so it cannot supply PP1 points for c.886del. PMID:30089731 reports one c.886del carrier in a BCC cohort with no affected relatives tested. No other fetched paper mentions the variant. Evidence is therefore insufficient to apply PP1 at any strength.
Rule
PALB2 CSPEC v1.2 PP1 (AD condition): Supporting LOD >=0.3 or LR >=2:1; Moderate LOD >=0.60 or LR >=4:1; Strong LOD >=1.26 or LR >=18:1. (AR condition: segregation in 1 / 2 / >=3 affected relatives.)
Evidence considered
ClinGen HOBPC EP PALB2 specification v1.2 (cspec) PP1 rules (AD condition): Supporting LOD >=0.3 or LR >=2:1; Moderate LOD >=0.60 or LR >=4:1; Strong LOD >=1.26 or LR >=18:1; quantitative co-segregation analysis (e.g., COOL Full-Likelihood Bayes with PALB2-approved defaults) is mandated; AR condition would require affected relatives carrying both proband variants.
PMID:25099575 (Antoniou et al. 2014): multicenter segregation/risk study of 154 families with 362 PALB2 loss-of-function carriers; c.886del is listed among the 48 different loss-of-function mutations in Figure 1A with no family count in parentheses (single family), and no variant-specific segregation count or LOD score is reported for c.886del - the paper's segregation and risk estimates are pooled across all mutations and cannot be assigned to this variant.
PMID:30089731 (Cho et al. 2018): one c.886del (p.M296X) carrier identified in a 61-patient high-frequency BCC cohort; no affected relatives tested and no segregation data reported.
The other fetched full-text papers (PMID:18053174, PMID:25529982, PMID:28279176, PMID:28779002, PMID:28858227) do not mention c.886del and contain no family-based evidence for it.
Still missing
No proband pedigree or affected-relatives testing accompanies this case; a computed LOD/Bayes factor (e.g., COOL FLB) or documented segregation in affected relatives for c.886del specifically is required before PP1 can be applied at any strength.
BS4Not assessed: no non-segregation or LOD data for c.886del; the PALB2 specification requires LOD <= -0.32 or Bayes factor <=0.48 for supporting BS4.
Details ▾Hide ▴
Reasoning
Under the PALB2 CSPEC v1.2, BS4 (lack of segregation in affected family members) is scored from quantitative segregation analysis: Supporting LOD <= -0.32 or LR <=0.48, Moderate LOD <= -0.64 or LR <=0.23, Strong (default) LOD <= -1.28 or LR <=0.053. No non-segregation observation or computed LOD/LR for c.886del exists in any case source: ClinVar VCV000143979 submissions report no family testing, PMID:25099575 provides no variant-specific segregation data (c.886del listed only in the pooled 154-family mutation inventory), PMID:30089731 reports a single carrier with no relatives tested, and no other fetched paper mentions the variant. Without affected-family data demonstrating absence of co-segregation, BS4 cannot be applied. The VCEP caveat also notes that phenocopies for common phenotypes such as cancer can mimic apparent lack of segregation, so BS4 would in any case require robust quantitative support.
Rule
PALB2 CSPEC v1.2 BS4: Supporting LOD <= -0.32 or LR <=0.48; Moderate LOD <= -0.64 or LR <=0.23; Strong LOD <= -1.28 or LR <=0.053.
Evidence considered
ClinGen HOBPC EP PALB2 specification v1.2 (cspec) BS4 rules: Supporting LOD <= -0.32 or LR <=0.48; Moderate LOD <= -0.64 or LR <=0.23; Strong (default) LOD <= -1.28 or LR <=0.053, reflecting lack of segregation in affected family members; VCEP caveat that phenocopies for common phenotypes (cancer) can mimic lack of segregation.
ClinVar VCV000143979 submission audit: no submission reports non-segregation, affected-relative testing, or any BS4-related evidence signal for c.886del.
PMID:25099575 and PMID:30089731 (the only fetched full-text papers mentioning c.886del) were reviewed for non-segregation data: neither reports any variant-specific family segregation results, so no LOD favoring absence of segregation can be derived.
The other fetched full-text papers (PMID:18053174, PMID:25529982, PMID:28279176, PMID:28779002, PMID:28858227) do not mention c.886del and contain no non-segregation evidence for it.
Still missing
No affected-family testing or non-segregation observation is available for c.886del; a computed LOD/LR (e.g., COOL FLB) or documented lack of segregation in affected relatives is required before BS4 can be applied at any strength.
Not applicable · 18· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: c.886del is a truncating frameshift (p.Met296Ter) with no splice impact (SpliceAI 0.018); PALB2 VCEP PS1 applies only to splice variants via its splicing table.
Details ▾Hide ▴
Reasoning
The governing PALB2 HBOP VCEP specification v1.2 (cspec) confines PS1 to splice variants: its card states applicability 'Applicable' but instructionsToUse 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2. Splicing: See PALB2 PS1 Table (PMID: 37352859)', with all three strength rows (Strong/Moderate/Supporting) keyed to 'Use PALB2 PS1 Splicing table'. NM_024675.4:c.886del is not a splice variant: it is a single-base deletion in exon 4 that shifts the reading frame and creates a premature termination codon (normalized NP_078951.2:p.(Met296Ter); ClinVar reports p.Lys295_Met296insTer), and SpliceAI predicts no splice impact (max delta 0.018, far below the VCEP's 0.1 BP4 / 0.2 PP3 splice thresholds). Classic same-amino-acid PS1 (identical protein change produced by a different nucleotide substitution at the same codon) is also structurally inapplicable: the reference ATG at codon 296 cannot be converted to any stop codon by a single-nucleotide substitution, the PS1 Table is splicing-scoped, and no established pathogenic variant producing the same protein-level consequence from an alternate nucleotide change is reported (PM5 comparator scan: 0 same-residue candidates). PS1 therefore cannot be applied to this variant class.
Evidence considered
PALB2 HBOP VCEP v1.2 (cspec) PS1 card: instructionsToUse 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2. Splicing: See PALB2 PS1 Table (PMID: 37352859)'; strength rules Strong/Moderate/Supporting all read 'Use PALB2 PS1 Splicing table' - PS1 is a splice-variant criterion in this framework.
c.886del is a frameshift deletion creating a premature stop at codon 296 (NP_078951.2:p.(Met296Ter); ClinVar variant title NM_024675.4(PALB2):c.886del p.Lys295_Met296insTer), not a splice-site change.
SpliceAI lookup for NM_024675.4:c.886del gives max delta 0.018 (DS_AG 0.018), below the VCEP's SpliceAI action thresholds (BP4 <=0.1, PP3 >=0.2), i.e., no predicted splice impact to which a PS1 splicing-table comparison could apply.
The PM5 comparator scan identified 0 same-residue candidate variants, and no established pathogenic variant generating the same p.Met296Ter protein consequence from a different nucleotide change is documented in the case evidence.
Reference codon ATG (Met296) cannot reach any stop codon (TGA/TAG/TAA) through a single-nucleotide substitution, so a classic substitution-based same-amino-acid PS1 comparator is structurally impossible at this residue.
PS2VCEPNot applicable: the PALB2 ClinGen specification disallows PS2 for autosomal dominant or recessive disease, and no de novo observation for c.886del exists.
Details ▾Hide ▴
Reasoning
The governing framework is the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification for PALB2 v1.2 (cspec), which explicitly lists PS2 as "Not Applicable" and instructs "Do not use for AD or AR disease." For autosomal dominant PALB2-related cancer predisposition the VCEP states that informative de novo occurrences have not yet been observed and, because breast cancer is relatively common and frequently appears sporadic, a de novo event is unlikely ever to be informative unless specific features of PALB2-related cancer predisposition are identified; for autosomal recessive Fanconi anemia, de novo occurrences are too rare to be informative and confirmation of phase in trans would essentially require parental testing. This case is a monoallelic truncating variant in the AD context (ClinVar condition "Familial cancer of breast"), and no de novo observation with or without confirmed parentage is reported for c.886del in ClinVar VCV000143979 submissions or in any fetched full-text paper. Because the specification disallows PS2 for both AD and AR PALB2 disease, the criterion is not applicable rather than merely unassessed, and no human-review trigger applies.
VCEP rule
PALB2 CSPEC v1.2: PS2 declared Not Applicable ("Do not use for AD or AR disease").
Evidence considered
ClinGen HOBPC EP PALB2 specification v1.2 (cspec): PS2 applicability "Not Applicable"; instructionsToUse "Do not use for AD or AR disease" - AD: informative de novo occurrences have not yet been observed and breast cancer is common/frequently an apparently sporadic event, so de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified; AR (Fanconi anemia): de novo occurrences too rare to be informative and confirmation in trans would require parental testing.
ClinVar VCV000143979 submission audit: all 5 submissions (SNPedia, LOVD, Ambry, Labcorp, Myriad) record germline/unknown origin with pathogenic assertions; no submission contains a de novo observation, parental-testing note, or PS2-related evidence signal.
Reviewed the only variant-positive full-text papers (PMID:25099575, PMID:30089731) for any de novo or parental-testing statement: PMID:25099575 lists c.886del among 48 PALB2 loss-of-function mutations in 154 families without proband-level de novo data; PMID:30089731 reports a single c.886del carrier in a 61-patient high-frequency BCC cohort with no parental testing or de novo observation.
Generic ACMG PS2 (Richards et al. 2015, PMID 25741868) background definition - de novo with confirmed maternity and paternity - would apply only in the absence of a specification; it is superseded here by the VCEP exclusion.
PS3VCEPNot applicable: the ClinGen HBOC VCEP PALB2 v1.2 specification explicitly marks PS3 as a non-applicable criterion for PALB2.
Details ▾Hide ▴
Reasoning
Governing framework: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOC) Expert Panel 'Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.2' (cspec doc 1526222356; framework_mode=vcep). In this specification PS3 is explicitly declared 'Not applicable' with no default strength and every strength partition (Stand Alone through Supporting) also marked 'Not applicable', i.e., the expert panel does not apply well-established functional studies supportive of a damaging effect to PALB2 variant classification. Independent of that framework-level bar, no validated variant-specific functional assay for NM_024675.4:c.886del (p.Met296Ter) exists in the case evidence: paper_extracts for all seven retrieved PALB2 full-text papers (PMID:18053174, 25529982, 28279176, 28779002, 28858227, 25099575, 30089731) show no in vitro/in vivo functional assay of this variant — c.886del appears only as a cohort case listing (PMID:30089731, Table 2) and as a loss-of-function mutation in a risk-analysis schematic (PMID:25099575, Figure 1A) — and the ClinVar submission audit records no functional-study criteria from any submitter. The loss-of-function impact of this truncating variant is instead addressed by the PALB2 PVS1 decision tree. PS3 therefore contributes no pathogenic weight and is recorded as not_applicable.
VCEP rule
ClinGen HBOC EP PALB2 VCEP v1.2 (cspec doc 1526222356): PS3 applicability = Not applicable (all strength partitions not applicable)
Evidence considered
ClinGen HBOC EP 'Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.2' (cspec doc 1526222356) lists PS3 with applicability 'Not applicable' and no default strength; all strength partitions (Stand Alone/Very Strong/Strong/Moderate/Supporting) are likewise 'Not applicable'.
The same PALB2 v1.2 ruleset is the operative case framework (framework_mode=vcep, precedence_rank 1), so generic ACMG PS3 is not substituted in.
paper_extracts review of the seven retrieved PALB2 full-text papers found no variant-specific functional (damaging-effect) assay for c.886del/p.(Met296Ter); PMID:30089731 reports the variant only as a pathogenic cohort listing in Table 2 and PMID:25099575 only within a loss-of-function mutation schematic in Figure 1A, with no functional assay data.
ClinVar submission audit for this variant (SCV002685305 Ambry Genetics 'criteria provided, single submitter'; SCV001193034 LOVD; SCV000188567 SNPedia) records no functional-study evidence or PS3-type criteria from any submitter.
The variant is a single-nucleotide deletion predicted to cause protein truncation p.(Met296Ter); in the PALB2 v1.2 specification such presumed loss-of-function events are evaluated through the PVS1 decision tree, not through PS3.
PM1VCEPNot applicable: the PALB2 VCEP v1.2 does not use PM1 (missense pathogenicity unconfirmed), lists no approved critical-functional domains, and c.886del is a truncating frameshift, not missense.
Details ▾Hide ▴
Reasoning
The governing PALB2 HBOP VCEP specification v1.2 (cspec) marks PM1 'Not applicable' with instructionsToUse 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease' and no applicable strength rules, so PM1 is not a usable criterion for PALB2 under this framework regardless of residue position. Consistently, the VCEP materials for this case contain no approved PALB2 critical-functional-domain table (the domain_tables key is empty), so there are no VCEP-sanctioned domain boundaries to test residue 296 against; the specification's only domain-level statement (in its PVS1 card) identifies the C-terminal WD40 beta-propeller and coiled-coil region as indispensable, and codon 296 is far N-terminal of those elements in any event. Independently, PM1 is a hotspot/critical-domain criterion designed for missense variants, whereas c.886del is a truncating frameshift (p.Met296Ter). PM1 is therefore not applicable to this variant.
Evidence considered
PALB2 HBOP VCEP v1.2 (cspec) PM1 card: applicability 'Not applicable', instructionsToUse 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease', no applicable strength rules - PM1 is excluded for the gene.
The VCEP materials carry no PALB2 entry in their domain_tables (empty), i.e., no VCEP-approved list of PALB2 critical functional domains exists to check residue 296 against.
The specification's PVS1 card notes that the WD40 beta-propeller and coiled-coil domain are considered indispensable for PALB2 function and that the last four residues (Y1183-H1186) seal the WD40 toroid; codon 296 lies N-terminal of, and is removed by, the truncation, which is consistent with loss-of-function but not with a PM1 missense-domain argument.
c.886del is a frameshift deletion predicted to produce p.Met296Ter (truncating), so it is not a missense variant in a putative critical domain, the situation PM1 is designed to evaluate.
PM4VCEPNot applicable: the PALB2 ClinGen VCEP specification v1.2 excludes PM4, and this 1-bp deletion causes a frameshift premature stop, not an in-frame protein-length change.
Details ▾Hide ▴
Reasoning
The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 specification v1.2 (cspec) explicitly declares PM4 'Not Applicable', so PM4 is not scored within this VCEP framework. Independently of the specification, the variant's mechanism is outside generic PM4 scope: generic PM4 (ACMG/AMP 2015) applies to protein-length changes caused by in-frame deletions/insertions in a non-repeat region or by stop-loss variants, whereas c.886del is a 1-bp deletion that shifts the reading frame and produces an immediate premature termination codon p.(Met296Ter), i.e., a truncating null event (PVS1 territory), not an in-frame protein-length alteration. Therefore no PM4 evidence applies.
VCEP rule
PALB2 VCEP v1.2 applicability: Not Applicable
Evidence considered
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 specification v1.2 (cspec) declares PM4 'Not Applicable' for PALB2.
Generic PM4 (ACMG/AMP 2015) covers protein-length changes from in-frame deletions/insertions in non-repeat regions or from stop-loss variants; c.886del is a 1-bp deletion causing a frameshift immediate premature stop p.(Met296Ter) (Mutalyzer normalization), which is a truncating event outside PM4's in-frame scope.
PM6VCEPNot applicable: the PALB2 ClinGen specification disallows PM6 for autosomal dominant or recessive disease, and no assumed-de-novo observation for c.886del exists.
Details ▾Hide ▴
Reasoning
The ClinGen HOBPC EP PALB2 specification v1.2 (cspec) lists PM6 as "Not Applicable" with the instruction "Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase." The VCEP thus excludes assumed-de-novo evidence (de novo without confirmed parentage) for both autosomal dominant PALB2-related cancer predisposition and autosomal recessive Fanconi anemia. No assumed-de-novo observation for c.886del is reported in any case source (ClinVar VCV000143979 submissions carry no such note, and neither variant-positive paper PMID:25099575 nor PMID:30089731 reports parental or de novo data). PM6 is therefore not applicable under the governing specification; the exclusion is framework-level and independent of this variant's data.
VCEP rule
PALB2 CSPEC v1.2: PM6 declared Not Applicable ("Do not use for AD or AR disease").
Evidence considered
ClinGen HOBPC EP PALB2 specification v1.2 (cspec): PM6 applicability "Not Applicable"; instructionsToUse "Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase."
ClinVar VCV000143979 submission audit: no submission reports an assumed de novo occurrence (unconfirmed parentage) or any PM6-related evidence signal for c.886del.
PMID:25099575 and PMID:30089731 (the only fetched full-text papers that mention c.886del) were reviewed and contain no de novo or parental-testing observations for this variant.
PP2VCEPNot applicable: the PALB2 VCEP v1.2 prohibits PP2 (missense mechanism not confirmed or refuted for PALB2), and c.886del is a truncating frameshift, not missense.
Details ▾Hide ▴
Reasoning
The governing PALB2 HBOP VCEP specification v1.2 (cspec) marks PP2 'Not applicable' with instructionsToUse 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2' and no applicable strength rules, so PP2 (a missense-mechanism criterion) is excluded for PALB2 under this framework. Independently, PP2 evaluates whether missense is a common disease mechanism in a gene with a low rate of benign missense variation, which presupposes a missense variant under review; c.886del is a truncating frameshift (p.Met296Ter), not a missense change. PP2 is therefore not applicable to this variant.
Evidence considered
PALB2 HBOP VCEP v1.2 (cspec) PP2 card: applicability 'Not applicable', instructionsToUse 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2', no applicable strength rules - PP2 is excluded for the gene.
PP2's original ACMG scope is 'Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease'; c.886del produces a premature stop (p.Met296Ter) and is not a missense variant, so the criterion cannot apply to this allele.
PP3N/ANot applicable: c.886del is a frameshift deletion creating p.Met296Ter, a truncating variant outside PP3's missense/SpliceAI scope.
Details ▾Hide ▴
Reasoning
not_applicable - scope-first. NM_024675.4:c.886del deletes a single coding nucleotide in exon 4 of PALB2, shifting the reading frame and creating an immediate premature termination codon, p.(Met296Ter) (ClinVar-style description p.(Lys295_Met296insTer); PMID:30089731 documents it as 'NM_024675:exon4:c.886delA (p.M296X)'; PMID:25099575 lists c.886del among the 48 loss-of-function mutations in its frameshift/deletion class). PP3 is calibrated for missense variants and, under the governing ClinGen HBOP VCEP PALB2 v1.2 (cspec), for splice-impact prediction (SpliceAI >= 0.2) restricted to silent, missense/in-frame, and intronic variants outside donor/acceptor 1,2 sites; it is never applied to frameshift/nonsense/truncating variants, whose functional impact is assessed by PVS1 (the VCEP further states that PP3 for splice predictions may not be applied in addition to a PVS1 code). A SpliceAI lookup result (max delta 0.018) is present in the case data but is deliberately not evaluated: no splice-impact score, whatever its value, can support PP3 for a protein-truncating variant.
Evidence considered
ClinGen HBOP VCEP PALB2 v1.2 (cspec) PP3 rule: missense predictions are not used for PALB2, and the splice-impact path (SpliceAI >= 0.2, SVI thresholds cited by the VCEP as Walker et al. 2023) applies only to silent, missense/in-frame, and intronic variants outside donor/acceptor 1,2 sites; frameshift/truncating variants are outside this scope and are instead assessed via PVS1, with PP3-for-splice explicitly not stackable on a PVS1 code.
NM_024675.4:c.886del is a single-nucleotide deletion in coding sequence producing a frameshift with immediate premature termination, p.(Met296Ter): PMID:30089731 (Table 2) reports the variant as NM_024675:exon4:c.886delA (p.M296X), and PMID:25099575 (Figure 1A) groups c.886del in the frameshift/deletion class of its 48 loss-of-function PALB2 mutations.
A SpliceAI lookup was retrieved for this case (max delta score 0.018) but was not evaluated for PP3 because the criterion is out of scope for a frameshift/truncating variant; the score is noted only to document that it was consciously excluded.
PP4VCEPNot applicable: the PALB2 VCEP v1.2 forbids PP4 for autosomal-dominant breast cancer, whose multiple genetic etiologies and lack of distinguishing features make phenotype-based support unusable.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP v1.2 marks PP4 as 'Not applicable', with instructionsToUse: 'Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes. For AR disorder, use PM3 for specific phenotype considerations.' This variant is assessed for the autosomal-dominant PALB2-related cancer predisposition phenotype (breast/ovarian/pancreatic cancer; MONDO:0700272), for which PP4 is explicitly disallowed because the phenotype lacks specificity for a single genetic etiology. No proband phenotype or family-history record accompanies this case that could independently support a generic-ACMG PP4 override.
VCEP rule
Not applicable per PALB2 VCEP v1.2: PP4 must not be used for the autosomal-dominant PALB2 cancer-predisposition phenotype.
Evidence considered
PALB2 VCEP v1.2 (cspec) marks PP4 'Not applicable'; instructionsToUse: 'Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes.'
Case input contains no proband phenotype or family-history record that could support phenotype specificity for PALB2-related cancer predisposition under a generic-ACMG PP4.
PP5VCEPNot applicable: the PALB2 VCEP v1.2 declares PP5 not applicable, and ClinVar VCV000143979 has no expert-panel classification, only laboratory submissions.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP v1.2 declares PP5 'Not applicable', superseding generic ACMG/AMP for this gene. Independently, the group rule permits PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification: VCV000143979 has zero expert-panel submissions (expert_panels is empty; submission audit reports 0 expert-panel submissions) and carries a 2-star aggregate 'Pathogenic' label built from three ordinary clinical-laboratory submissions (Ambry, Labcorp/Invitae, Myriad) plus LOVD and SNPedia entries, none of which is an expert-panel assertion. The aggregate ClinVar label and ordinary laboratory submissions must never trigger PP5.
VCEP rule
PP5 is not applicable under PALB2 VCEP v1.2; under the group rule it would additionally require an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
Evidence considered
PALB2 VCEP v1.2 (cspec) lists PP5 as 'Not applicable'.
ClinVar VCV000143979: expert_panels is empty and the submission audit reports 0 expert-panel submissions; review status is 'criteria provided, multiple submitters, no conflicts' (2 stars) with submissions from clinical laboratories (Ambry, Labcorp/Invitae, Myriad), LOVD and SNPedia; no exact-variant expert-panel Pathogenic/Likely pathogenic classification exists, so PP5 cannot be triggered.
BS3VCEPNot applicable: the ClinGen HBOC VCEP PALB2 v1.2 specification explicitly marks BS3 as a non-applicable criterion for PALB2.
Details ▾Hide ▴
Reasoning
Governing framework: ClinGen HBOC Expert Panel PALB2 Specification v1.2 (cspec doc 1526222356; framework_mode=vcep). In this specification BS3 is explicitly declared 'Not applicable' with no default strength assignment and all strength partitions marked 'Not applicable', i.e., the expert panel does not apply well-established functional studies showing no damaging effect to PALB2 variant classification; benign RNA 'no aberrant defect' observations are handled under the BP7(RNA) code framework in this specification rather than BS3. Consistent with this, no variant-specific non-damaging functional assay data for NM_024675.4:c.886del (p.Met296Ter) exists in the case evidence: the seven retrieved full-text papers (PMID:18053174, 25529982, 28279176, 28779002, 28858227, 25099575, 30089731) contain no wild-type-function assay result for this variant (paper_extracts confirm no variant-level functional data of either direction), and no ClinVar submitter reports functional criteria. BS3 therefore contributes no benign weight and is recorded as not_applicable.
VCEP rule
ClinGen HBOC EP PALB2 VCEP v1.2 (cspec doc 1526222356): BS3 applicability = Not applicable (all strength partitions not applicable)
Evidence considered
ClinGen HBOC EP 'Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.2' (cspec doc 1526222356) lists BS3 with applicability 'Not applicable' and no default strength; all strength partitions (Stand Alone/Very Strong/Strong/Moderate/Supporting) are likewise 'Not applicable'.
The PALB2 v1.2 specification routes observed lack of aberrant RNA/splicing effect to the BP7(RNA) code with variable weight (curator discretion on assay quality), not to BS3; BS3 as such is not used for PALB2.
paper_extracts review of the seven retrieved PALB2 full-text papers found no non-damaging/wild-type functional assay result for c.886del/p.(Met296Ter) in any paper; the variant is absent from functional data in all seven (only cohort listing in PMID:30089731 Table 2 and LoF schematic in PMID:25099575 Figure 1A).
ClinVar submission audit for this variant (SCV002685305 Ambry Genetics; SCV001193034 LOVD; SCV000188567 SNPedia) records no functional-study evidence or BS3-type criteria from any submitter.
BP1N/ANot applicable: the PALB2 VCEP BP1 supporting rule applies only to missense variants, and c.886del p.(Met296Ter) is a truncating frameshift.
Details ▾Hide ▴
Reasoning
The governing PALB2 HBOP VCEP specification v1.2 (cspec) makes BP1 'Applicable' but scopes it strictly to missense variants: instructionsToUse 'Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are not yet confirmed or refuted but are thought to be exceedingly rare. Given the very low likelihood that missense variants are pathogenic, this rule applies to all missense variants in PALB2', with the Supporting rule 'Apply to all missense variants.' NM_024675.4:c.886del is not a missense variant - it is a frameshift deletion creating a premature termination codon (p.Met296Ter / p.Lys295_Met296insTer), i.e., a truncating loss-of-function allele of the very class that causes PALB2-related disease. The benign-supporting logic of BP1 (a single amino-acid substitution is unlikely to be pathogenic in a predominantly truncating-mechanism gene) has no bearing on a truncating allele. BP1 is therefore not applicable to this variant.
Evidence considered
PALB2 HBOP VCEP v1.2 (cspec) BP1 card: 'Given the very low likelihood that missense variants are pathogenic, this rule applies to all missense variants in PALB2'; Supporting rule 'Apply to all missense variants.'
c.886del is a frameshift deletion predicted to produce p.Met296Ter (ClinVar: p.Lys295_Met296insTer), a truncating loss-of-function allele, so the missense-scoped BP1 rule is not triggered for this variant.
BP2VCEPNot applicable: the PALB2 HBOP VCEP v1.2 declares BP2 not applicable, and no in-trans or in-cis observation of c.886del exists.
Details ▾Hide ▴
Reasoning
The governing PALB2 HBOP VCEP specification v1.2 (cspec) explicitly sets BP2 applicability to 'Not Applicable' (instructionsToUse: 'Use ATM PM3/BP2 table', with no applicable strength rules), so in-trans/in-cis co-occurrence observations are not scored as benign evidence for PALB2 under this framework; this is consistent with PALB2 being an incompletely penetrant, moderate-risk autosomal-dominant cancer susceptibility gene in which co-occurrence with other pathogenic variants is expected and therefore not benign-informative. Even under the original ACMG/AMP BP2 definition (observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern), no source in the case evidence reports c.886del in cis or in trans with any pathogenic PALB2 variant, and no phased observations exist. BP2 is therefore not applicable here.
Evidence considered
PALB2 HBOP VCEP v1.2 (cspec) BP2 entry: applicability 'Not applicable', defaultStrength 'Benign Supporting', instructionsToUse 'Use ATM PM3/BP2 table', and no applicable strength rules - the framework does not permit BP2 as benign evidence for PALB2.
Original ACMG BP2 definition consulted for completeness: 'Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.' No case source reports c.886del in cis or in trans with any pathogenic PALB2 variant, and no phase data exist, so generic BP2 could not be met either.
VCEP rationale context (BP5 entry, 'Do not use'): PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population, supporting the framework's decision not to treat co-occurrence as benign.
BP3VCEPNot applicable: the PALB2 ClinGen VCEP specification v1.2 excludes BP3, and the variant is a frameshift deletion, not an in-frame repeat-region indel.
Details ▾Hide ▴
Reasoning
The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 specification v1.2 (cspec) explicitly declares BP3 'Not Applicable', so BP3 is not scored within this VCEP framework. Independently of the specification, the variant is outside generic BP3 scope: generic BP3 (ACMG/AMP 2015) applies to in-frame deletions/insertions in a repetitive region without a known function, whereas c.886del is a 1-bp deletion producing a frameshift premature stop p.(Met296Ter), not an in-frame indel in a repeat region. Therefore no BP3 evidence applies.
VCEP rule
PALB2 VCEP v1.2 applicability: Not Applicable
Evidence considered
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 specification v1.2 (cspec) declares BP3 'Not Applicable' for PALB2.
Generic BP3 (ACMG/AMP 2015) applies to in-frame deletions/insertions in a repetitive region without known function; c.886del is a 1-bp out-of-frame deletion causing p.(Met296Ter), not an in-frame repeat-region indel.
BP4N/ANot applicable: c.886del causes frameshift truncation (p.Met296Ter), not a missense or splice-region change, so BP4's SpliceAI no-impact path does not apply.
Details ▾Hide ▴
Reasoning
not_applicable - scope-first. Under the governing ClinGen HBOP VCEP PALB2 v1.2 (cspec), BP4's only usable rule is the converse splice-impact path - no predicted impact via splicing (SpliceAI <= 0.1) - and the VCEP instructs that the wrong type of computational evidence must not be applied to the wrong mechanism ('Do not apply for missense variants'; missense in-silico predictors are unusable for PALB2). c.886del is a frameshift single-nucleotide deletion with immediate premature termination, p.(Met296Ter): the variant's impact is protein truncation, not a missense or splicing effect that these predictors were calibrated to assess, and a 'no splice impact' call cannot mean 'no impact on gene/gene product' for an allele that truncates the protein. The retrieved SpliceAI max delta of 0.018 is therefore not evaluated, and BP4 is not_applicable - not met and not not_met - because the variant class is upstream of the evidence the criterion requires.
Evidence considered
ClinGen HBOP VCEP PALB2 v1.2 (cspec) BP4 rule: 'Missense: Do not use. Splicing: No predicted impact via splicing (SpliceAI <= 0.1). Do not apply for missense variants', with VCEP instructions noting that splice analysis for all variant types is only a caution about variants that may also affect splicing and that computational evidence for one mechanism (protein vs RNA) must not be applied to the other.
NM_024675.4:c.886del is a frameshift single-nucleotide deletion producing immediate premature termination p.(Met296Ter): PMID:30089731 (Table 2) reports NM_024675:exon4:c.886delA (p.M296X), and PMID:25099575 (Figure 1A) classes c.886del as a frameshift/deletion loss-of-function PALB2 mutation; a truncating allele's impact is not what the BP4 splice-no-impact predictor path was calibrated to assess.
A SpliceAI lookup was retrieved for this case (max delta score 0.018) but was not evaluated for BP4: BP4 is out of scope for a frameshift/truncating variant regardless of the score's value.
BP5VCEPNot applicable: the PALB2 VCEP v1.2 declares BP5 not applicable; co-occurring pathogenic variants are expected given moderate penetrance and do not count as benign evidence.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP v1.2 marks BP5 as 'Not applicable'. Its guidance explains that cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g., BRCA1 and BRCA2), and because PALB2 has moderate penetrance it will naturally co-occur with other pathogenic variants more frequently, so an alternate-molecular-basis observation cannot be used as benign evidence for PALB2. No proband-level data documenting an alternate molecular basis of disease accompany this case in any event, and no likelihood-ratio-style BP5 threshold exists in this VCEP.
VCEP rule
Not applicable per PALB2 VCEP v1.2: BP5 (variant found in a case with an alternate molecular basis for disease) is not used for PALB2.
Evidence considered
PALB2 VCEP v1.2 (cspec) marks BP5 'Not applicable'; instructionsToUse notes that multiple pathogenic variants have been observed with no noticeable phenotype difference and that PALB2's moderate penetrance makes co-occurring pathogenic variants expected, so alternate-molecular-basis observations are not benign evidence for PALB2.
No proband-level alternate-molecular-basis (second pathogenic variant) data accompany this case.
BP6VCEPNot applicable: the PALB2 VCEP v1.2 declares BP6 not applicable, and ClinVar VCV000143979 has no expert-panel benign classification (Pathogenic, laboratory submissions only).
Details ▾Hide ▴
Reasoning
The PALB2 VCEP v1.2 declares BP6 'Not applicable', superseding generic ACMG/AMP for this gene. Independently, the group rule permits BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification: VCV000143979 contains no expert-panel submissions, its aggregate classification is Pathogenic (not benign), and the underlying assertions are ordinary laboratory submissions, which must never trigger BP6.
VCEP rule
BP6 is not applicable under PALB2 VCEP v1.2; under the group rule it would additionally require an exact-variant ClinVar expert-panel Benign or Likely benign classification.
Evidence considered
PALB2 VCEP v1.2 (cspec) lists BP6 as 'Not applicable'.
ClinVar VCV000143979 aggregate classification is Pathogenic with zero expert-panel submissions; there is no exact-variant expert-panel Benign/Likely benign classification, so BP6 cannot be triggered.
BP7N/ANot applicable: BP7 is reserved for synonymous and deep intronic variants; c.886del is a protein-truncating frameshift (p.Met296Ter).
Details ▾Hide ▴
Reasoning
not_applicable - scope-first. Under the governing ClinGen HBOP VCEP PALB2 v1.2 (cspec), BP7 is restricted to synonymous (silent) variants and to deep intronic variants (further than, but not including, +7 from the donor site and -21 from the acceptor site), with the BP7(RNA) subrule likewise limited to observed lack of aberrant RNA for silent substitutions and intronic variants. NM_024675.4:c.886del is not synonymous: it is a frameshift single-nucleotide deletion in exon 4 producing immediate premature termination, p.(Met296Ter), documented as exon 4 c.886delA (p.M296X) by PMID:30089731 and as a frameshift/deletion-class loss-of-function mutation by PMID:25099575. Because the variant changes the reading frame and protein sequence rather than being a silent change, BP7 is not_applicable.
Evidence considered
ClinGen HBOP VCEP PALB2 v1.2 (cspec) BP7 rule: 'Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively', plus BP7(RNA) for observed lack of aberrant RNA in silent substitutions and intronic variants.
NM_024675.4:c.886del is not a synonymous variant: it is a frameshift single-nucleotide deletion creating immediate premature termination p.(Met296Ter), reported as NM_024675:exon4:c.886delA (p.M296X) in PMID:30089731 (Table 2) and grouped with frameshift/deletion loss-of-function mutations in PMID:25099575 (Figure 1A).
Because BP7's scope is limited to variants that do not alter the encoded protein sequence, no synonymous-variant evidence is required or evaluated for this frameshift allele.
AF 2.5e-06 · 4 / 1,613,998 alleles · 0 hom · FAF 7.9e-07
European (non-Finnish)4 / 1,179,946
3.4e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,348 alleles · 0 hom
European (non-Finnish)1 / 113,674
8.8e-06
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.47832e-06; MAF= 0.00025%, 4/1613998 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.38999e-06; MAF= 0.00034%, 4/1179946 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97855e-06; MAF= 0.00040%, 1/251348 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79709e-06; MAF= 0.00088%, 1/113674 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -288 bp
0.000
SpliceAI acceptor gainat +494 bp
0.018
SpliceAI donor lossat +29 bp
0.002
SpliceAI donor gainat +82 bp
0.008
Pangolin splice lossmagnitude shown
-0.052
Pangolin splice gain
0.027
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: c.886del is a frameshift deletion creating p.Met296Ter, a truncating variant outside PP3's missense/SpliceAI scope.
Details ▾Hide ▴
Reasoning
not_applicable - scope-first. NM_024675.4:c.886del deletes a single coding nucleotide in exon 4 of PALB2, shifting the reading frame and creating an immediate premature termination codon, p.(Met296Ter) (ClinVar-style description p.(Lys295_Met296insTer); PMID:30089731 documents it as 'NM_024675:exon4:c.886delA (p.M296X)'; PMID:25099575 lists c.886del among the 48 loss-of-function mutations in its frameshift/deletion class). PP3 is calibrated for missense variants and, under the governing ClinGen HBOP VCEP PALB2 v1.2 (cspec), for splice-impact prediction (SpliceAI >= 0.2) restricted to silent, missense/in-frame, and intronic variants outside donor/acceptor 1,2 sites; it is never applied to frameshift/nonsense/truncating variants, whose functional impact is assessed by PVS1 (the VCEP further states that PP3 for splice predictions may not be applied in addition to a PVS1 code). A SpliceAI lookup result (max delta 0.018) is present in the case data but is deliberately not evaluated: no splice-impact score, whatever its value, can support PP3 for a protein-truncating variant.
Evidence considered
ClinGen HBOP VCEP PALB2 v1.2 (cspec) PP3 rule: missense predictions are not used for PALB2, and the splice-impact path (SpliceAI >= 0.2, SVI thresholds cited by the VCEP as Walker et al. 2023) applies only to silent, missense/in-frame, and intronic variants outside donor/acceptor 1,2 sites; frameshift/truncating variants are outside this scope and are instead assessed via PVS1, with PP3-for-splice explicitly not stackable on a PVS1 code.
NM_024675.4:c.886del is a single-nucleotide deletion in coding sequence producing a frameshift with immediate premature termination, p.(Met296Ter): PMID:30089731 (Table 2) reports the variant as NM_024675:exon4:c.886delA (p.M296X), and PMID:25099575 (Figure 1A) groups c.886del in the frameshift/deletion class of its 48 loss-of-function PALB2 mutations.
A SpliceAI lookup was retrieved for this case (max delta score 0.018) but was not evaluated for PP3 because the criterion is out of scope for a frameshift/truncating variant; the score is noted only to document that it was consciously excluded.
BP4N/ANot applicable: c.886del causes frameshift truncation (p.Met296Ter), not a missense or splice-region change, so BP4's SpliceAI no-impact path does not apply.
Details ▾Hide ▴
Reasoning
not_applicable - scope-first. Under the governing ClinGen HBOP VCEP PALB2 v1.2 (cspec), BP4's only usable rule is the converse splice-impact path - no predicted impact via splicing (SpliceAI <= 0.1) - and the VCEP instructs that the wrong type of computational evidence must not be applied to the wrong mechanism ('Do not apply for missense variants'; missense in-silico predictors are unusable for PALB2). c.886del is a frameshift single-nucleotide deletion with immediate premature termination, p.(Met296Ter): the variant's impact is protein truncation, not a missense or splicing effect that these predictors were calibrated to assess, and a 'no splice impact' call cannot mean 'no impact on gene/gene product' for an allele that truncates the protein. The retrieved SpliceAI max delta of 0.018 is therefore not evaluated, and BP4 is not_applicable - not met and not not_met - because the variant class is upstream of the evidence the criterion requires.
Evidence considered
ClinGen HBOP VCEP PALB2 v1.2 (cspec) BP4 rule: 'Missense: Do not use. Splicing: No predicted impact via splicing (SpliceAI <= 0.1). Do not apply for missense variants', with VCEP instructions noting that splice analysis for all variant types is only a caution about variants that may also affect splicing and that computational evidence for one mechanism (protein vs RNA) must not be applied to the other.
NM_024675.4:c.886del is a frameshift single-nucleotide deletion producing immediate premature termination p.(Met296Ter): PMID:30089731 (Table 2) reports NM_024675:exon4:c.886delA (p.M296X), and PMID:25099575 (Figure 1A) classes c.886del as a frameshift/deletion loss-of-function PALB2 mutation; a truncating allele's impact is not what the BP4 splice-no-impact predictor path was calibrated to assess.
A SpliceAI lookup was retrieved for this case (max delta score 0.018) but was not evaluated for BP4: BP4 is out of scope for a frameshift/truncating variant regardless of the score's value.
BP7N/ANot applicable: BP7 is reserved for synonymous and deep intronic variants; c.886del is a protein-truncating frameshift (p.Met296Ter).
Details ▾Hide ▴
Reasoning
not_applicable - scope-first. Under the governing ClinGen HBOP VCEP PALB2 v1.2 (cspec), BP7 is restricted to synonymous (silent) variants and to deep intronic variants (further than, but not including, +7 from the donor site and -21 from the acceptor site), with the BP7(RNA) subrule likewise limited to observed lack of aberrant RNA for silent substitutions and intronic variants. NM_024675.4:c.886del is not synonymous: it is a frameshift single-nucleotide deletion in exon 4 producing immediate premature termination, p.(Met296Ter), documented as exon 4 c.886delA (p.M296X) by PMID:30089731 and as a frameshift/deletion-class loss-of-function mutation by PMID:25099575. Because the variant changes the reading frame and protein sequence rather than being a silent change, BP7 is not_applicable.
Evidence considered
ClinGen HBOP VCEP PALB2 v1.2 (cspec) BP7 rule: 'Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively', plus BP7(RNA) for observed lack of aberrant RNA in silent substitutions and intronic variants.
NM_024675.4:c.886del is not a synonymous variant: it is a frameshift single-nucleotide deletion creating immediate premature termination p.(Met296Ter), reported as NM_024675:exon4:c.886delA (p.M296X) in PMID:30089731 (Table 2) and grouped with frameshift/deletion loss-of-function mutations in PMID:25099575 (Figure 1A).
Because BP7's scope is limited to variants that do not alter the encoded protein sequence, no synonymous-variant evidence is required or evaluated for this frameshift allele.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
7 paper records listed. 3 cited in the classification.
Cited in the classification
Breast-cancer risk in families with mutations in PALB2.
Antoniou AC et al. · 2014 Aug 7
This paper is a multicenter segregation analysis of breast-cancer risk in 154 families (362 members) carrying deleterious germline PALB2 loss-of-function mutations. The exact variant c.886del is explicitly listed in Figure 1A among the 48 different loss-of-function mutations reported in the study (frameshift/deletion class); no family count is shown in parentheses after c.886del, indicating it was present in only a single family. No variant-specific clinical, segregation, or frequency data are reported for c.886del individually; the paper's risk estimates (cumulative breast-cancer risk 35% by age 70 for female carriers; ~8-9x relative risk) apply to the pooled loss-of-function mutation cohort. Families with PALB2 missense or VUS variants were excluded, so inclusion of c.886del implies it was classified as a deleterious loss-of-function allele.
→ PVS1 · very strong→ PM5 · supportingNames this variant
Among the 154 families, there were 48 different loss-of-function mutations in PALB2 (Fig. 1A, and Table S3 in the Supplementary Appendix).
Location Results, Families paragraph (page 499); variant listed in Figure 1A (PALB2 gene structure and mutations schematic)
Context Multicenter (14 centers) family study; 154 families with 362 PALB2 loss-of-function mutation carriers (311 women, 51 men); modified complex segregation analysis using Mendel v3.3 to estimate age-specific breast-cancer risk; ascertainment-adjusted likelihoods
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
Decker B et al. · 2017 Nov
The paper does not name PALB2 c.886del (p.M296*) or report individual carrier counts for it, so no variant-specific data exist here. The relevant evidence is at the class level: in a population-based study sequencing PALB2 (plus ATM, CHEK2, XRCC2) in 13,087 breast cancer cases and 5,488 controls, protein-truncating variants in PALB2 as a group (frameshift, stop/gain, canonical splice) were associated with the highest breast cancer risk of the four genes (OR=4.69, 95% CI 2.27-9.68, p=6.9e-6). Most PALB2 truncating variants were rare (19/35 as singletons). Risk for PALB2 truncation carriers did not differ by ER status and showed no association with family history. Three more-common C-terminal truncations (in the final 280 codons) had a lower combined OR=3.57, whereas all other truncating variants had OR=5.79 (95% CI 2.10-16.0). As c.886del is not individually reported, its contribution to these aggregate estimates cannot be determined from this paper.
Of the four genes, truncating variants in PALB2 were associated with the highest BC risk, with an estimated OR=4.69 (95% CI 2.27 to 9.68, p=6.9×10−6)(table 1 and figure 2).
Location Results, 'BC risks associated with ATM, CHEK2 and PALB2 truncating variants' (Table 1 and Figure 2)
Context Population-based case-control study (SEARCH, East Anglia UK): 13,087 breast cancer cases and 5,488 controls; targeted sequencing of coding exons and intron-exon boundaries of ATM, CHEK2, PALB2 and XRCC2; protein-truncating variants (frameshift, stop/gain, canonical splice) analysed as a group
Frequent basal cell cancer development is a clinical marker for inherited cancer susceptibility.
Cho HG et al. · 2018 Aug 9
The paper reports a germline PALB2 nonsense/frameshift variant, NM_024675:exon4:c.886delA (p.M296X, here given as p.M296*), identified in one subject within a 61-patient 'high-frequency BCC' cohort (individuals with 6+ biopsy-confirmed basal cell carcinomas in a 10-year period, top 5% of BCC patients at Stanford). The variant was one of 13 pathogenic mutations found in 12 of 61 (19.7%) subjects across 12 DNA repair/cancer-susceptibility genes (APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2), classified as pathogenic per ACMG/AMP criteria via ClinVar and HGMD, and confirmed by Sanger sequencing. PALB2 is noted as participating in homologous recombination DNA repair. No individual-level clinical data (cancer history, segregation, or functional assay) specific to this PALB2 variant carrier is provided beyond its listing in Table 2.
→ PVS1 · very strong→ PM5 · supportingNames this variant
Location Table 2 (Pathogenic mutations identified in the high-frequency BCC cohort), with cohort description in Results, paragraph 2
Context 61-subject retrospective cohort with frequent BCC (6+ BCCs over 10 years, top 5% of BCC patients at Stanford 2005-2015); germline DNA from saliva, targeted capture sequencing of 29 genes (Fulgent Genetics Focus Cancer panel, mean coverage 53.8x), pathogenic calls per ACMG/AMP criteria using ClinVar (June 2015) and HGMD Professional (2016.4), confirmed by Sanger sequencing
Other recorded publications
Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.
The paper does not mention the variant c.886del (p.M296*) or any variant at that position. It studies PALB2 in French-Canadian breast cancer patients and identifies a different truncating founder mutation, Q775X (c.2323C>T), in 3 of ~406 cases, absent in 6,448 Quebec newborn controls; it reviews prior literature listing eight other distinct PALB2 truncating mutations associated with increased breast cancer risk. No functional assay data relevant to c.886del or codon 296 are reported.
Until now, eight distinct truncating mutations have been associated with an increased risk for breast cancer (I76fs, L531fs, G796X, T841fs, A995fs, W1038X, N1039fs, and Y1183X) [9,10,12,13].
Discussion, paragraph 2 (variant list); Results and Discussion for Q775X founder data
A novel PALB2 truncating mutation in an Italian family with male breast cancer.
This paper does not mention the PALB2 c.886del (p.M296*) variant; no data on it (frequency, segregation, or function) appears anywhere in the text. The study is instead a PALB2 mutational screen of 8 male-breast-cancer cases selected from 181 Italian hereditary breast/ovarian cancer probands, which identified a single novel truncating mutation, c.1285_1286delAinsTC (p.I429SfsX12), in exon 4 (1/8 cases, 12.5%), confirmed at the mRNA level by RT-PCR. Gene-level relevance only: the paper argues PALB2 truncating mutations can contribute to hereditary breast cancer in families with MBC, but provides no evidence specific to c.886del/M296*.
Mutation analysis of the PALB2 gene showed the presence of a mutation in 1/8 (12.5%) breast cancer patients. This mutation, not previously described, was named c.1285_1286delAinsTC (p.I429SfsX12).
Results, paragraph 2 (mutation also shown in Table I, patient 6)
PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland.
This paper does not mention the variant c.886del / p.(M296*) anywhere. The study screened the full PALB2 coding region by NGS in 460 BRCA1/2-mutation-negative Polish breast and/or ovarian cancer patients and identified three truncating PALB2 mutations (c.172_175delTTGT, c.347insT, c.509_510delGA) in 7/460 (1.5%) patients. Since the exact variant is absent, only gene-level context applies (germline inactivating PALB2 mutations confer increased breast/ovarian cancer risk). No functional, segregation, or frequency data relevant to c.886del / p.(M296*) is reported.
In this group, we identified seven unrelated carriers (1.5%) of the three PALB2 truncating mutations: c.172_175delTTGT (n = 4), c.347insT (n = 1), and c.509_510delGA (n = 2) (Table 1).
Results, NGS analysis (variant c.886del not found in paper; gene-level findings only)
The Role of PALB2 in the DNA Damage Response and Cancer Predisposition.
Review article on PALB2 biology and cancer predisposition; it does not mention c.886del (p.M296*) or any variant at codon 296. Its only variant-level relevance is generic: PALB2 germline truncating variants are associated with elevated breast cancer risk (Rahman et al. 2007: found in 1.1% of BRCA1/2-negative familial BC cases, relative risk 2.3-fold vs non-carriers), show incomplete penetrance typical of moderate-risk genes, and biallelic PALB2 mutations cause Fanconi anemia subtype FA-N. No functional assay, case-level, or segregation data specific to c.886del is presented, so the paper offers no direct evidence for this exact variant.
Rahman and colleagues (2007) reported that PALB2 germline truncating variants occurred in 1.1% of patients from a subset of familial BC cases which tested negative for BRCA1 and BRCA2 alterations [21]. In the same study, PALB2 was reported to have an incomplete penetrance pattern, typical of moderate cancer risk susceptibility genes, and was estimated that the relative risk for PALB2 truncating variant carriers was 2.3-fold higher than non-carriers [21].
Section 2.1 (Cancer Predisposition), first paragraph
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.14 / 1,613,998 recorded allelesOpen source ↗
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.47832e-06; MAF= 0.00025%, 4/1613998 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.38999e-06; MAF= 0.00034%, 4/1179946 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97855e-06; MAF= 0.00040%, 1/251348 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79709e-06; MAF= 0.00088%, 1/113674 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories). (ClinVarID = 143979)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55161955, n = 16 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 8.0.0.
The current version is 11.0.07.
Re-running queues a fresh interpretation; the result replaces this page when complete.
Re-runs are not free. Blank draws on today's public interpretation allowance; with a code, it uses one of that code's uses.