The PALB2 NM_024675.4:c.2488del (NP_078951.2:p.(Glu830SerfsTer21)) frameshift variant has not previously been reported in somatic cancers (COSMIC). This variant is predicted to result in an absent or disrupted protein product. Based on available guidelines, this variant is considered to be Likely Pathogenic.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
This variantScenario
BenignPathogenic
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
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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.
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01The reasoning
How it was classified
The recorded framework is ClinGen PALB2 VCEP v1.3. 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, very strong: the exon-5 frameshift creates a premature stop at residue 850, upstream of the VCEP's His1184 PVS1 boundary, with no downgrade rule applying.
PM5Supporting
PM5 · supporting
Met at Supporting: the frameshift terminates before p.His1184, satisfying the VCEP PM5 truncation cutoff, subject to confirming PVS1 Very Strong.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Likely Pathogenic: PVS1 (very strong) plus PM5 (supporting) satisfy Rule19 of the PALB2 VCEP Version 1.3 framework.
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
9 / 1,614,118 alleles
gnomAD v4.1: 9 / 1,614,118 alleles. Recorded AF 5.5758e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.9794e-06; MAF= 0.00040%, 1/251294 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
ACMG/AMP criteria under ClinGen PALB2 VCEP v1.3, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 3 not met · 5 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 strength because the exon-5 frameshift creates a premature termination at residue 850, upstream of the VCEP's His1184 boundary, and the VCEP provides no applicable downgrade.
PM4 and BP3 are not applicable because the PALB2 Version 1.3 CSPEC explicitly marks both criteria Not Applicable.
Within the requested codon/residue/domain criteria, PS1, PM1, PP2, and BP1 are not applicable under the PALB2 VCEP rules because the variant is a frameshift or the criteria are explicitly excluded; PM5 is Supporting only if the required PVS1 Very Strong prerequisite is confirmed.
Within this requested group, PP4, PP5, BP5, and BP6 are explicitly not applicable under the PALB2 VCEP. PS4 cannot be assessed for this exact variant because the available case-control result is an aggregate truncating-variant analysis rather than variant-specific evidence.
All three requested criteria are outside their governing PALB2 VCEP variant-type scope for this coding frameshift.
The available SpliceAI result is not reassigned to PP3, BP4, or BP7 because predictor evidence cannot extend a criterion beyond the VCEP rule that names it.
BA1 and BS1 are not met because the gnomAD v4.1 grpmax FAF is 0.005136%, below both VCEP thresholds.
PM2 is not met because the highest gnomAD v4.1 subpopulation frequency is 0.0098799%, above the VCEP threshold of 0.000333%.
BS2 is not assessed because no qualifying healthy-adult observation was available and gnomAD population cohorts are explicitly excluded; the governing PALB2 PM3/BS2 table had no matching variant entry.
No criteria match.
Met · 2
PVS1Very strongVCEPMet, very strong: the exon-5 frameshift creates a premature stop at residue 850, upstream of the VCEP's His1184 PVS1 boundary, with no downgrade rule applying.
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Reasoning
NM_024675.4:c.2488del is a frameshift in coding exon 5 of the clinically relevant PALB2 transcript, producing NP_078951.2:p.(Glu830SerfsTer21) / p.(E830Sfs*21), with a predicted premature termination at residue 850 in a 1186-amino-acid protein. The VCEP recognizes frameshift variants as PVS1-eligible null variants in PALB2, considers the annotated transcript biologically relevant, and states that stop gains upstream of His1184 are PVS1 regardless of NMD status. The predicted termination at residue 850 is upstream of His1184 and is not at the extreme 3' end; no named VCEP downgrade rule applies. The PALB2_PVS1_v1.3.pdf file was searched for c.2488del, p.Glu830SerfsTer21, and p.E830Sfs*21, with no variant-specific table entry found; the governing guide and case consequence facts nevertheless directly support full-strength PVS1.
VCEP rule
Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease ... In keeping with that, we have considered that all presumed LoF events (PVS1 decision tree specifications) occur in biologically relevant transcript(s). ... For that reason, variants introducing stop gains upstream of His1184 are considered PVS1, regardless of NMD status.
Evidence considered
Case consequence facts: NM_024675.4:c.2488del is a frameshift in exon 5 and produces NP_078951.2:p.(Glu830SerfsTer21) / p.(E830Sfs*21).
The normalized protein consequence predicts the first altered residue at 829 and the last predicted residue at 850 in the 1186-amino-acid PALB2 protein.
PALB2 PVS1 guide: null variants include frameshift variants in a gene where loss of function is a known disease mechanism; the guide states that the clinically relevant transcript is NM_024675.3 and all presumed LoF events occur in biologically relevant transcript(s).
PALB2 PVS1 guide, footnote A: variants introducing stop gains upstream of His1184 are considered PVS1 regardless of NMD status.
Still missing
PALB2_PVS1_v1.3.pdf was searched for c.2488del, p.Glu830SerfsTer21, and p.E830Sfs*21; no variant-specific entry was found.
PM5SupportingVCEPMet at Supporting: the frameshift terminates before p.His1184, satisfying the VCEP PM5 truncation cutoff, subject to confirming PVS1 Very Strong.
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Reasoning
The PALB2 VCEP PM5 rule applies at Supporting strength to all NMD-prone truncating variants receiving PVS1 at Very Strong when the premature termination codon is upstream of p.His1184. NM_024675.4:c.2488del is a frameshift, p.(Glu830SerfsTer21)/p.(E830Sfs*21), producing a premature termination upstream of p.His1184. The PALB2 PVS1 guide defines frameshift variants as null variants in a gene where loss of function is a known disease mechanism and states that presumed loss-of-function events occur in biologically relevant transcripts. This supports the VCEP PM5 truncating-variant pathway, but the case bundle does not contain an explicit independent PVS1 strength call of Very Strong; human review is retained for that prerequisite.
VCEP rule
* DNA Variants: Apply to all NMD-prone, truncating variants receiving PVS1 (must be at VeryStrong) with premature termination codons upstream of p.His1184
Evidence considered
vcep_materials.json, PM5 rule: DNA variants receive PM5 Supporting when they are NMD-prone truncating variants receiving PVS1 at VeryStrong with premature termination codons upstream of p.His1184.
pvs1_variant_assessment.json: NM_024675.4:c.2488del is a frameshift with protein consequence NP_078951.2:p.(E830Sfs*21), in exon 5.
PALB2_PVS1_v1.3.pdf: PVS1 covers null variants including frameshifts in a gene where loss of function is a known mechanism of disease; the default transcript is biologically relevant for presumed loss-of-function events.
Still missing
The case evidence does not provide an explicit independent PVS1 strength assignment of Very Strong, which is a PM5 prerequisite.
PM2VCEPNot met: the highest gnomAD v4.1 subpopulation frequency is 0.0098799%, exceeding the PALB2 PM2 threshold of 0.000333%.
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Reasoning
The PALB2 VCEP permits PM2 Supporting when frequency is <=1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency, with an exception for a single observation confined to one subpopulation. The highest observed subpopulation frequency is 0.0098799% in gnomAD v4.1 South Asians (9/91,094 alleles), and the variant is also present in other gnomAD populations/datasets; this exceeds 0.000333%, so PM2 is not met. The older non-cancer exome and genome-only records are also above the threshold in their highest subpopulations: 0.0032759% in gnomAD v2.1 non-cancer exomes and 0.020816% in gnomAD v3.1 non-cancer genomes.
VCEP rule
Frequency ≤ 1/300,000 (**0.000333%**) in gnomAD subpopulation with the highest frequency ... Exception: If >0.000333% but n=1 in a single subpopulation (not present in any other subpopulation), that is sufficiently rare and PM2_supporting would apply.
Evidence considered
PALB2 VCEP v1.3 CSPEC PM2 rule: Frequency <= 1/300,000 (0.000333%) in gnomAD subpopulation with the highest frequency; exception applies only when frequency is above 0.000333% but n=1 in a single subpopulation and absent from every other subpopulation.
gnomAD v4.1: South Asian subpopulation 9/91,094 alleles, AF 9.879904e-05 = 0.0098799%, homozygotes 0; total 9/1,614,118 alleles.
gnomAD v2.1 non-cancer exomes: South Asian subpopulation 1/30,526 alleles, AF 3.275896e-05 = 0.0032759%, homozygotes 0; total 1/236,758 alleles.
gnomAD v3.1 non-cancer genomes: South Asian subpopulation 1/4,804 alleles, AF 0.0002081599 = 0.020816%, homozygotes 0; total 1/147,992 alleles.
BA1VCEPNot met: gnomAD v4.1 grpmax FAF is 0.005136%, below the PALB2 VCEP BA1 threshold of >0.1%.
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Reasoning
The PALB2 VCEP defines BA1 as grpmax filtering allele frequency >0.1% in gnomAD. The highest available gnomAD v4.1 grpmax FAF is 5.136e-05, equivalent to 0.005136%, which is below the VCEP threshold; therefore BA1 is not met.
VCEP rule
Grpmax Filtering AF **>.1%** in gnomAD
Evidence considered
PALB2 VCEP v1.3 CSPEC BA1 rule: Grpmax Filtering AF >.1% in gnomAD.
gnomAD v4.1 record for NC_000016.9:g.23629665del / 16-23629665-TC-T: grpmax FAF 5.136e-05 (0.005136%); total AF 5.5758e-06 from 9/1,614,118 alleles and 0 homozygotes.
BS1VCEPNot met: gnomAD v4.1 grpmax FAF is 0.005136%, below the PALB2 VCEP BS1 threshold of >0.01%.
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Reasoning
The PALB2 VCEP defines BS1 as grpmax filtering allele frequency >0.01% in gnomAD. The highest available gnomAD v4.1 grpmax FAF is 5.136e-05, equivalent to 0.005136%, below 0.01%; therefore BS1 is not met. The South Asian subpopulation frequency is 0.0098799%, but BS1 specifically requires grpmax filtering AF and this value does not meet the stated grpmax threshold.
VCEP rule
Grpmax Filtering AF **>.01%** in gnomAD
Evidence considered
PALB2 VCEP v1.3 CSPEC BS1 rule: Grpmax Filtering AF >.01% in gnomAD.
gnomAD v4.1 record for NC_000016.9:g.23629665del / 16-23629665-TC-T: grpmax FAF 5.136e-05 (0.005136%); highest South Asian subpopulation AF 9.8799e-05 (0.0098799%), with 9 alleles and 0 homozygotes.
PS4VCEPNot assessed: aggregate PALB2 truncating variants met OR 4.69 and p=6.9×10⁻⁶ thresholds, but c.2488del was not variant-specific in that study.
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Reasoning
The VCEP PS4 rule requires a case-control study with p-value ≤.05 and either an odds ratio, hazard ratio, or relative risk ≥3, or a lower 95% confidence interval ≥1.5. PMID:28779002 reports aggregate PALB2 protein-truncating-variant risk (OR=4.69, 95% CI 2.27–9.68, p=6.9×10⁻⁶) in 13,087 cases and 5,488 controls: 6.9×10⁻⁶ ≤ 0.05? yes; 4.69 ≥ 3? yes; 2.27 ≥ 1.5? yes. However, the paper does not report NM_024675.4:c.2488del or p.(Glu830SerfsTer21) specifically; it analyzes truncating variants in aggregate. Therefore, the available evidence does not establish PS4 for this exact variant under the VCEP-only rule, and variant-specific case-control evidence is required.
VCEP rule
Case-control studies; p-value ≤.05 **and** (Odds ratio, hazard ratio, or relative risk ≥3 **or** lower 95% CI ≥1.5).
Evidence considered
ClinGen PALB2 VCEP v1.3 PS4 rule: case-control studies require p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥3 or lower 95% CI ≥1.5).
PMID:28779002, Results: aggregate PALB2 truncating variants had OR=4.69, 95% CI 2.27–9.68, p=6.9×10⁻⁶ in 13,087 breast cancer cases and 5,488 controls; c.2488del was not reported specifically.
Still missing
Variant-specific case-control counts or a variant-specific association estimate for NM_024675.4:c.2488del are unavailable.
PM3VCEPNot assessed: the VCEP PM3 table has no c.2488del entry, and no affected-proband phase evidence assigns any PM3 points.
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Reasoning
The PALB2 v1.3 PM3 rule requires a recessive-disease observation in trans with a pathogenic variant and assigns points from the Fanconi Anemia PM3 table. The governing file PALB2_PM3_BS2_1.3.pdf was searched for c.2488del, p.Glu830SerfsTer21, and p.E830Sfs*21; no entry for this variant was found. The available case evidence does not document an affected Fanconi Anemia proband, a pathogenic variant in trans or cis, phase, homozygosity, or an applicable proband-level observation. PMID:17200671 describes biallelic PALB2 variants in Fanconi Anemia but does not report this variant, so it cannot supply PM3 points for this case.
VCEP rule
For recessive disorders, detected in trans with a pathogenic variant
Evidence considered
PALB2_PM3_BS2_1.3.pdf, PM3 section and Fanconi Anemia PM3 table: the file was searched under c.2488del, p.Glu830SerfsTer21, and p.E830Sfs*21, with no matching variant row found.
Case evidence bundle: no affected-proband PM3 observation, phase result, pathogenic variant in trans, homozygous observation, or pre-assigned PM3 code was identified for this variant.
PMID:17200671, Results paragraph describing biallelic PALB2 mutations in Fanconi Anemia: relevant disease-context evidence, but the exact variant is not reported and no case-specific PM3 points can be assigned.
Still missing
No entry for c.2488del, p.Glu830SerfsTer21, or p.E830Sfs*21 was found in PALB2_PM3_BS2_1.3.pdf.
No case-level affected Fanconi Anemia proband observation, phase determination, pathogenic variant in trans, homozygous observation, or PM3 point assignment is available.
PP1VCEPNot assessed: no variant-specific LOD, Bayes factor, or confirmed affected-relative segregation is available for c.2488del against the VCEP PP1 thresholds.
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Reasoning
The VCEP permits PP1 at Supporting when the autosomal-dominant condition has LOD ≥0.3 or Bayes factor (LR) ≥2:1, and at Moderate or Strong with higher specified values; the case evidence does not provide a variant-specific LOD, Bayes factor, or confirmed segregation in affected relatives for NM_024675.4:c.2488del. PMID:25099575 reports segregation analysis across 154 families and 48 PALB2 loss-of-function variants but does not identify this variant, so it cannot establish PP1 for this case.
VCEP rule
* AD Condition: LOD ≥0.3 or Bayes Factor (LR) ≥2:1
* AR Condition: Segregation in 1 affected relative
Evidence considered
ClinGen PALB2 VCEP PP1 rule: AD Supporting requires LOD ≥0.3 or Bayes Factor (LR) ≥2:1; Moderate requires LOD ≥0.60 or Bayes Factor (LR) ≥4:1; Strong requires LOD ≥1.26 or Bayes Factor (LR) ≥18:1.
Antoniou et al., PMID:25099575, analyzed 154 families with 48 PALB2 loss-of-function mutations but the extracted report does not explicitly mention c.2488del or p.(E830Sfs*21), so it supplies no variant-specific segregation result for this case.
Still missing
Variant-specific family genotypes and phenotypes, affected-relative segregation count, and/or LOD or Bayes factor are unavailable.
BS2VCEPNot assessed: no qualifying healthy-adult observation was available, and the VCEP excludes gnomAD population cohorts from BS2.
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Reasoning
The PALB2 VCEP requires an observation in a healthy adult with the relevant inheritance pattern and states that population-based cohorts such as gnomAD must not be used for BS2. No qualifying clinical or research-cohort healthy-adult observation was available. The governing PALB2_PM3_BS2_1.3.pdf table was searched for c.2488del, p.Glu830SerfsTer21, and p.E830Sfs*21; no entry for this variant was found.
VCEP rule
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. ... Do not use for individuals in population based cohorts, such as gnomAD
Evidence considered
PALB2 VCEP v1.3 BS2 rule text states that BS2 is based on a healthy adult individual with full penetrance expected at an early age and instructs: Do not use for individuals in population based cohorts, such as gnomAD.
PALB2_PM3_BS2_1.3.pdf, BS2 section and Fanconi Anemia PM3|BS2 tables: no matching row was found for c.2488del, p.Glu830SerfsTer21, or p.E830Sfs*21.
The available gnomAD records are population-based data and therefore were not used as BS2 evidence.
Still missing
No qualifying healthy-adult clinical or research-cohort observation was available.
No entry for c.2488del, p.Glu830SerfsTer21, or p.E830Sfs*21 was found in PALB2_PM3_BS2_1.3.pdf.
BS4VCEPNot assessed: no variant-specific non-segregation result, LOD, or Bayes factor is available for the VCEP BS4 thresholds.
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Reasoning
The VCEP BS4 thresholds require a segregation LOD or Bayes factor: Strong at LOD ≤ -1.28 or LR ≤.053:1, Moderate at LOD ≤ -.64 or LR ≤.23, and Supporting at LOD ≤-.32 or LR ≤.48. The available case evidence contains no variant-specific non-segregation observations, unaffected relatives tested, LOD, or Bayes factor, so BS4 cannot be evaluated.
VCEP rule
Strong: LOD ≤ -1.28 or Bayes Factor (LR) ≤.053:1; Moderate: LOD ≤ -.64 or Bayes Factor (LR) ≤.23; Supporting: LOD ≤-.32 or Bayes Factor (LR) ≤.48
Evidence considered
ClinGen PALB2 VCEP CSPEC BS4 thresholds are LOD ≤ -1.28 or LR ≤.053:1 for Strong, LOD ≤ -.64 or LR ≤.23 for Moderate, and LOD ≤-.32 or LR ≤.48 for Supporting; no corresponding case result is reported.
Still missing
Variant-specific unaffected-relative testing and non-segregation data, with LOD or Bayes factor, are unavailable.
Not applicable · 18· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: c.2488del is a frameshift, while PALB2 PS1 is restricted to missense-excluded and splicing-table pathways.
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Reasoning
The PALB2 VCEP defines PS1 as the same amino acid change as a previously established pathogenic variant, but explicitly directs that missense changes not be used and directs splicing variants to the PS1 splicing table. This variant is a frameshift, NM_024675.4:c.2488del, p.(Glu830SerfsTer21)/p.(E830Sfs*21), not a missense or splicing variant. The governing PALB2_PS1_1.3.pdf was searched for c.2488del, p.Glu830SerfsTer21, and p.E830Sfs*21; no variant-specific entry was found.
VCEP rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change ... • Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2. ... • Splicing: Use PALB2 PS1 Splicing table for splicing variants with similar predictions or observations of splice defect. (PMID: 36865205)
Evidence considered
PALB2_PS1_1.3.pdf, PS1 rule: the variant is a frameshift rather than a missense or splicing variant.
PALB2_PS1_1.3.pdf search for c.2488del, p.Glu830SerfsTer21, and p.E830Sfs*21 returned no matching variant-specific entry.
PS3VCEPNot applicable: the PALB2 VCEP v1.3 explicitly designates PS3 as not applicable, so functional assay evidence cannot receive PS3.
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Reasoning
The PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP Version 1.3 explicitly marks PS3 as not applicable. Therefore, no protein or RNA functional study can be used to assign PS3 under this governing framework, regardless of the general PALB2 functional evidence reviewed. A published PALB2 functional study (PMID:17200671) evaluated other biallelic truncating variants and did not report NM_024675.4:c.2488del or p.(Glu830SerfsTer21).
VCEP rule
For protein, see detailed notes on ATM-specific assays; For RNA use code PVS1_O and modulate strength based on assay quality and quantity (curator discretion).
Evidence considered
PALB2 VCEP v1.3 CSPEC PS3 entry: applicability is "Not applicable" and its instructions state, "For protein, see detailed notes on ATM-specific assays; For RNA use code PVS1_O and modulate strength based on assay quality and quantity (curator discretion)."
Reid et al. 2007 (PMID:17200671): biallelic truncating PALB2 variants in Fanconi anemia cases showed absent PALB2 protein and complementation of mitomycin-C-induced G2 arrest, but NM_024675.4:c.2488del was not reported.
PM1VCEPNot applicable: the PALB2 VCEP CSPEC explicitly marks PM1 as Not Applicable, with no PALB2 domain table supplied.
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Reasoning
The PALB2 VCEP CSPEC marks PM1 as Not Applicable. The case's vcep_materials.json has no authoritative domain_tables entry for PALB2, and the governing PM1 applicability setting independently excludes this criterion.
VCEP rule
Not Applicable
Evidence considered
vcep_materials.json, PALB2 PM1 CSPEC entry: applicability is Not Applicable.
PM4VCEPNot applicable: the PALB2 Version 1.3 CSPEC explicitly marks PM4 as Not Applicable.
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Reasoning
The PALB2 Version 1.3 CSPEC entry explicitly marks PM4 as Not Applicable. The frameshift consequence therefore does not receive PM4 under the governing VCEP framework.
VCEP rule
Not Applicable
Evidence considered
PALB2 Version 1.3 CSPEC criterion entry for PM4: applicability is Not Applicable.
PP3N/ANot applicable: PALB2 PP3 covers silent, missense/in-frame, and specified intronic variants, whereas c.2488del is a frameshift.
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Reasoning
The variant is a frameshift, NM_024675.4:c.2488del, p.(Glu830SerfsTer21). The PALB2 VCEP PP3 splicing pathway applies only to silent, missense/in-frame, and specified intronic variants; frameshift variants are outside its scope, so PP3 is not applicable. The available SpliceAI max delta score of 0.037 is not used because the governing rule does not cover this variant type.
VCEP rule
* Missense: Do not use.
* Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
The PALB2 VCEP CSPEC identifies c.2488del as a frameshift, p.(Glu830SerfsTer21).
The VCEP PP3 splicing rule names silent, missense/in-frame, and intronic variants outside donor and acceptor sites; it does not include frameshift variants.
SpliceAI max delta score = 0.037 is present in the case evidence but is not criterion evidence for PP3 because this variant is outside the PP3 rule's stated scope.
PP4VCEPNot applicable: the VCEP excludes PP4 for hereditary breast cancer because genetic heterogeneity prevents a phenotype specific to one genetic etiology.
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Reasoning
The VCEP marks PP4 not applicable for PALB2-related autosomal-dominant cancer predisposition because breast cancer has genetic heterogeneity and no features readily distinguish hereditary from sporadic causes. For autosomal-recessive disease, the VCEP directs phenotype considerations to PM3 rather than PP4.
VCEP rule
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
Evidence considered
ClinGen PALB2 VCEP v1.3 PP4 instruction excludes PP4 for autosomal-dominant breast cancer and directs autosomal-recessive phenotype considerations to PM3.
PP5VCEPNot applicable: the VCEP explicitly prohibits PP5, regardless of the available pathogenic ClinVar assertions.
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Reasoning
The VCEP explicitly designates PP5 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
ClinGen PALB2 VCEP v1.3 PP5 instruction prohibits use of this criterion.
BS3VCEPNot applicable: the PALB2 VCEP v1.3 explicitly designates BS3 as not applicable, so functional assay evidence cannot receive BS3.
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Reasoning
The PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP Version 1.3 explicitly marks BS3 as not applicable. Therefore, no protein or RNA functional study can be used to assign BS3 under this governing framework, regardless of the general PALB2 functional evidence reviewed. A published PALB2 functional study (PMID:17200671) evaluated other biallelic truncating variants and did not report NM_024675.4:c.2488del or p.(Glu830SerfsTer21).
VCEP rule
For protein, see detailed notes on ATM-specific assays; For RNA use code BP7_O and modulate strength based on assay quality and quantity (curator discretion).
Evidence considered
PALB2 VCEP v1.3 CSPEC BS3 entry: applicability is "Not applicable" and its instructions state, "For protein, see detailed notes on ATM-specific assays; For RNA use code BP7_O and modulate strength based on assay quality and quantity (curator discretion)."
Reid et al. 2007 (PMID:17200671): biallelic truncating PALB2 variants in Fanconi anemia cases showed absent PALB2 protein and complementation of mitomycin-C-induced G2 arrest, but NM_024675.4:c.2488del was not reported.
BP1N/ANot applicable: BP1 applies to missense variants, whereas c.2488del is a frameshift.
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Reasoning
The PALB2 VCEP BP1 rule applies to all missense variants. NM_024675.4:c.2488del is a frameshift, p.(Glu830SerfsTer21)/p.(E830Sfs*21), so it lies outside the variant type named by the governing rule.
VCEP rule
Apply to all missense variants.
Evidence considered
vcep_materials.json, PALB2 BP1 rule: Apply to all missense variants.
pvs1_variant_assessment.json: the reviewed variant is classified as a frameshift with p.(E830Sfs*21).
BP2VCEPNot applicable: the PALB2 VCEP Version 1.3 CSPEC explicitly marks BP2 not applicable.
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Reasoning
The PALB2 Version 1.3 CSPEC entry explicitly marks BP2 as not applicable. Therefore, no BP2 assessment is made from any observed or unobserved allelic relationship.
VCEP rule
Not applicable
Evidence considered
PALB2 Version 1.3 CSPEC BP2 entry: applicability is recorded as Not applicable and the strength rules are not applicable.
BP3VCEPNot applicable: the PALB2 Version 1.3 CSPEC explicitly marks BP3 as Not Applicable.
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Reasoning
The PALB2 Version 1.3 CSPEC entry explicitly marks BP3 as Not Applicable. The frameshift consequence and any repeat-region context therefore do not receive BP3 under the governing VCEP framework.
VCEP rule
Not Applicable
Evidence considered
PALB2 Version 1.3 CSPEC criterion entry for BP3: applicability is Not Applicable.
BP4N/ANot applicable: BP4's no-splice-impact pathway cannot negate the truncating effect of this frameshift, regardless of its SpliceAI score.
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Reasoning
The variant is a frameshift, NM_024675.4:c.2488del, p.(Glu830SerfsTer21). Under the governing PALB2 VCEP rule, BP4's splice pathway is for variants with no predicted splice impact and explicitly excludes missense variants; for a frameshift, no predicted splice impact does not negate the truncating protein effect, so BP4 is not applicable. The SpliceAI max delta score of 0.037 is therefore not used for BP4.
VCEP rule
* Missense: Do not use.
* Splicing: No predicted impact via splicing (SpliceAI **≤0.1**). Do not apply for missense variants.
Evidence considered
The PALB2 VCEP CSPEC identifies c.2488del as a frameshift, p.(Glu830SerfsTer21).
The VCEP BP4 rule is limited to no predicted splice impact via SpliceAI ≤0.1 and states that it does not apply for missense variants; the rule does not provide a BP4 path for frameshift variants.
SpliceAI max delta score = 0.037 is present in the case evidence but is not used for BP4 because BP4 is not applicable to a truncating frameshift variant.
BP5VCEPNot applicable: the VCEP prohibits BP5 because PALB2 moderate penetrance and observed multiple pathogenic variants undermine this criterion's use.
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Reasoning
The VCEP marks BP5 not applicable and instructs that it should not be used because multiple pathogenic variants can occur without a noticeable phenotype difference and PALB2 has moderate penetrance, making co-occurrence more frequent in the general population.
VCEP rule
Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.
Evidence considered
ClinGen PALB2 VCEP v1.3 BP5 instruction prohibits use because multiple pathogenic variants may occur without a noticeable phenotype difference and PALB2 has moderate penetrance.
BP6VCEPNot applicable: the VCEP explicitly prohibits BP6, regardless of any reputable-source benign assertion.
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Reasoning
The VCEP explicitly designates BP6 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
ClinGen PALB2 VCEP v1.3 BP6 instruction prohibits use of this criterion.
BP7N/ANot applicable: BP7 covers synonymous and specified deep-intronic variants, whereas c.2488del is a coding frameshift.
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Reasoning
The variant is a frameshift, NM_024675.4:c.2488del, p.(Glu830SerfsTer21), not a synonymous substitution or an intronic variant at the locations covered by the PALB2 VCEP BP7 rule. BP7 is therefore not applicable; no RNA evidence is needed to establish that scope exclusion.
VCEP rule
* BP7: 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.
* BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
The PALB2 VCEP CSPEC identifies c.2488del as a coding frameshift, p.(Glu830SerfsTer21).
The VCEP BP7 rule limits the computational path to synonymous and deep intronic variants defined as beyond +7 and beyond -21 from donor and acceptor sites; this frameshift is outside those variant classes.
AF 5.6e-06 · 9 / 1,614,118 alleles · 0 hom · FAF 5.1e-05
South Asian9 / 91,094
9.9e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 4e-06 · 1 / 251,294 alleles · 0 hom
South Asian1 / 30,616
3.3e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.5758e-06; MAF= 0.00056%, 9/1614118 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.8799e-05; MAF= 0.00988%, 9/91094 alleles, homozygotes = 0); grpmax FAF= 5.136e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.9794e-06; MAF= 0.00040%, 1/251294 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat +294 bp
0.027
SpliceAI acceptor gainat +155 bp
0.000
SpliceAI donor lossat -25 bp
0.037
SpliceAI donor gainat -131 bp
0.020
Pangolin splice lossmagnitude shown
-0.167
Pangolin splice gain
0.005
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: PALB2 PP3 covers silent, missense/in-frame, and specified intronic variants, whereas c.2488del is a frameshift.
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Reasoning
The variant is a frameshift, NM_024675.4:c.2488del, p.(Glu830SerfsTer21). The PALB2 VCEP PP3 splicing pathway applies only to silent, missense/in-frame, and specified intronic variants; frameshift variants are outside its scope, so PP3 is not applicable. The available SpliceAI max delta score of 0.037 is not used because the governing rule does not cover this variant type.
VCEP rule
* Missense: Do not use.
* Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
The PALB2 VCEP CSPEC identifies c.2488del as a frameshift, p.(Glu830SerfsTer21).
The VCEP PP3 splicing rule names silent, missense/in-frame, and intronic variants outside donor and acceptor sites; it does not include frameshift variants.
SpliceAI max delta score = 0.037 is present in the case evidence but is not criterion evidence for PP3 because this variant is outside the PP3 rule's stated scope.
BP4N/ANot applicable: BP4's no-splice-impact pathway cannot negate the truncating effect of this frameshift, regardless of its SpliceAI score.
Details ▾Hide ▴
Reasoning
The variant is a frameshift, NM_024675.4:c.2488del, p.(Glu830SerfsTer21). Under the governing PALB2 VCEP rule, BP4's splice pathway is for variants with no predicted splice impact and explicitly excludes missense variants; for a frameshift, no predicted splice impact does not negate the truncating protein effect, so BP4 is not applicable. The SpliceAI max delta score of 0.037 is therefore not used for BP4.
VCEP rule
* Missense: Do not use.
* Splicing: No predicted impact via splicing (SpliceAI **≤0.1**). Do not apply for missense variants.
Evidence considered
The PALB2 VCEP CSPEC identifies c.2488del as a frameshift, p.(Glu830SerfsTer21).
The VCEP BP4 rule is limited to no predicted splice impact via SpliceAI ≤0.1 and states that it does not apply for missense variants; the rule does not provide a BP4 path for frameshift variants.
SpliceAI max delta score = 0.037 is present in the case evidence but is not used for BP4 because BP4 is not applicable to a truncating frameshift variant.
BP7N/ANot applicable: BP7 covers synonymous and specified deep-intronic variants, whereas c.2488del is a coding frameshift.
Details ▾Hide ▴
Reasoning
The variant is a frameshift, NM_024675.4:c.2488del, p.(Glu830SerfsTer21), not a synonymous substitution or an intronic variant at the locations covered by the PALB2 VCEP BP7 rule. BP7 is therefore not applicable; no RNA evidence is needed to establish that scope exclusion.
VCEP rule
* BP7: 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.
* BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
The PALB2 VCEP CSPEC identifies c.2488del as a coding frameshift, p.(Glu830SerfsTer21).
The VCEP BP7 rule limits the computational path to synonymous and deep intronic variants defined as beyond +7 and beyond -21 from donor and acceptor sites; this frameshift is outside those variant classes.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
The paper does not explicitly mention PALB2 c.2488del or NP_078951.2:p.(Glu830SerfsTer21). It reports that, in a population-based sequencing study of breast cancer cases and controls, PALB2 protein-truncating variants as a group were associated with an estimated breast cancer odds ratio of 4.69 (95% CI 2.27–9.68; p=6.9×10⁻⁶). The study identified 35 PALB2 truncating variants, most of which were rare; 19/35 were observed as singletons. The paper does not provide variant-specific observations, functional assay results, segregation data, or a population frequency for c.2488del.
Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.
Reid S et al. · 2007
The paper does not report PALB2 c.2488del or p.(E830Sfs*21). It reports biallelic truncating PALB2 mutations in individuals with Fanconi anemia subtype FA-N and childhood cancer; patient-derived cells showed absent PALB2 protein, and restoring wild-type PALB2 reversed mitomycin-C-induced G2-phase arrest.
Breast-cancer risk in families with mutations in PALB2.
Antoniou AC et al. · 2014
The study evaluated breast-cancer risk in 154 families carrying 48 different PALB2 loss-of-function mutations and included 362 mutation carriers, but it does not explicitly mention PALB2 c.2488del or p.(E830Sfs*21).
Among the 154 families, there were 48 different loss-of-function mutations in PALB2 (Fig. 1A, and Table S3 in the Supplementary Appendix).
Results, Families; page 499
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
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= 5.5758e-06; MAF= 0.00056%, 9/1614118 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.8799e-05; MAF= 0.00988%, 9/91094 alleles, homozygotes = 0); grpmax FAF= 5.136e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.9794e-06; MAF= 0.00040%, 1/251294 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (12 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 230859)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 11.0.05.
The current version is 11.0.07.
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