Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
This variantScenario
BenignPathogenic
Uncertain.The recorded classification is uncertain significance.
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.
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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 (Supporting): absent from gnomAD v4 (AF=0), satisfying the VCEP frequency threshold of <=1/300,000 (0.000333%).
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
Met (Supporting): the VCEP applies BP1 to all missense variants; this is a confirmed missense change (p.Glu990Asp).
Recorded classification: Uncertain significance
VUS: conflicting evidence, with exactly one Pathogenic.Supporting criterion (PM2, gnomAD v4 AF=0) and one Benign.Supporting criterion (BP1, all missense variants) under VCEP v1.2 Rule 31.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
ACMG/AMP criteria under ClinGen PALB2 VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 6 not met · 4 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The ClinGen HBOC VCEP PALB2 v1.2 specification is the governing framework (framework_mode 'vcep', precedence_rank 1) and was used for all three criteria in this group.
PVS1 is not met: c.2970A>T is a missense substitution (p.(Glu990Asp)) in exon 9 - not a null variant (no nonsense, frameshift, initiation-codon, canonical +/-1,2 splice, or deletion) - and SpliceAI predicts no splice impact (max delta 0.026), so neither the null-variant nor the splice-defect arm of the PALB2 PVS1 decision tree applies.
PM4 is not applicable by VCEP rule: the spec restricts PM4 to stop-loss variants only, and this allele is a missense with no protein length change.
BP3 is not applicable by VCEP rule: small in-frame losses are not an established mechanism for PALB2 and PALB2 is not considered to have repetitive regions without known function; the allele is not an in-frame indel.
No literature was available for this group: literature_pass.json reports 0 PMIDs and paper_extracts.json / fulltext_map.json are empty, so no paper_findings entries were created.
Governing framework is the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP) Expert Panel PALB2 specification v1.2 (cspec), used in preference to generic ACMG/AMP.
BP1 (Benign Supporting) is met: the VCEP applies BP1 to all PALB2 missense variants, and c.2970A>T is a confirmed missense (p.Glu990Asp).
PM1 and PP2 are not applicable: the PALB2 HBOP VCEP v1.2 explicitly marks both criteria 'Not Applicable', and vcep_materials.json domain_tables is empty so no approved PALB2 critical functional domain list exists to evaluate.
PM5 is not applicable: the VCEP redefines PM5 as a truncation-cutoff rule (frameshifting/truncating variants with PTCs upstream of p.Tyr1183, or NMD-prone splice variants with PVS1_VS(RNA)); a missense variant is outside its scope, and the pm5_candidates artifact confirms classic same-residue PM5 was not eligible.
PS1 is not met: the VCEP PS1 is splicing-table-based and this variant has no predicted splice impact (SpliceAI max delta 0.026); no established pathogenic same-amino-acid comparator (classic PS1) was found in ClinVar, pm5_candidates, or literature (no PMIDs available).
No functional-domain or hotspot evidence applies: the variant is not in a statistically significant cancer hotspot (Cancer Hotspots) and COSMIC/OncoKB provide no variant-specific record.
Governing framework: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel (HBOPC VCEP) specifications for PALB2 v1.2 (cspec doc 1526222356), used in place of generic ACMG/AMP for all four criteria in this group.
PS2 and PM6 are not_applicable by explicit VCEP determination: informative de novo occurrences have not yet been observed for PALB2, and for AD PALB2-related cancer predisposition de novo events are unlikely to ever be informative given breast cancer frequently occurs as an apparently sporadic event; de novo AR (FA-N) occurrences are likewise considered non-informative.
PP1 and BS4 are applicable but cannot be assessed: the PALB2 VCEP mandates quantitative co-segregation analysis (LOD score or Bayes factor), and this case bundle contains no proband/pedigree/segregation data of any kind (variant absent from ClinVar, 0 PMIDs in literature_pass, empty fulltext_map and paper_extracts).
This group therefore contributes no pathogenic or benign evidence to the overall classification; PP1 and BS4 would need family segregation testing data (pedigree with affected-relative genotypes and/or LOD/LR calculation) before they can be evaluated.
PS3 and BS3 are both declared 'Not Applicable' in the governing ClinGen HBOP VCEP PALB2 specification v1.2 (cspec), which takes precedence over generic ACMG/AMP for this gene; neither criterion is scored.
Independently of the framework declaration, no variant-specific functional assay evidence for PALB2 c.2970A>T (p.Glu990Asp) exists in the case bundle (0 PMIDs; empty paper_extracts and fulltext_map; OncoKB 'Unknown Oncogenic Effect' with no variant-specific functional data), so neither PS3 nor BS3 could be met under any framework.
No publications were reviewed for the functional group because no relevant PMIDs or full-text papers were available in the evidence bundle.
The governing framework is the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification for PALB2 version 1.2 (cspec doc 1526222356); it takes precedence over generic ACMG/AMP for this gene.
PS4 is the only applicable criterion in this group: it requires a case-control study with p-value <= 0.05 AND (OR/HR/RR >= 3 OR lower 95% CI >= 1.5). No case-control or prevalence data exist for c.2970A>T (literature pass: 0 PMIDs; no full texts or paper extracts), so PS4 is not_assessed and flagged for human review.
PP4, PP5, BP5, and BP6 are all marked Not Applicable by the PALB2 VCEP v1.2 specification, so they contribute no evidence regardless of variant-specific data.
PP5 and BP6 additionally cannot be triggered because the exact variant is absent from ClinVar (no submissions, no expert-panel classification), which fails the exact-variant expert-panel requirement for both criteria.
No phenotype-specific or case-control evidence is available from any source in the bundle, so this group neither supports nor opposes pathogenicity.
Both criteria in this group are allelic/phase-based criteria. PM3 cannot be scored because the case bundle contains no proband-level observations: no affected individual carrying the variant, no second PALB2 allele, and no trans/cis phase determination; the variant is absent from ClinVar and no literature was identified (0 PMIDs, empty paper_extracts/fulltext_map).
BP2 is not applicable because the governing PALB2 VCEP v1.2 specification explicitly marks it 'Not Applicable'; the gene-specific VCEP framework takes precedence over generic ACMG/AMP rules.
No allelic evidence (pathogenic variant in trans or in cis) could be identified from any source in the bundle, and no inference was made from any other source's final classification.
PP3 not met: splice-based PP3 is evaluable for this missense/in-frame variant per PALB2 VCEP v1.2, but SpliceAI max delta score 0.026 is well below the VCEP ≥0.2 threshold; the missense in-silico path is explicitly barred by the VCEP ('Missense: Do not use').
BP4 not applicable: PALB2 VCEP v1.2 explicitly states 'Do not apply for missense variants'; although SpliceAI 0.026 is ≤0.1, low splice impact cannot be used as benign-supporting evidence for a missense variant under the governing framework.
BP7 not applicable: the variant is missense (p.Glu990Asp), and PALB2 VCEP v1.2 restricts BP7 to synonymous and deep intronic variants; no RNA assay evidence is available for the BP7(RNA) path.
Population criteria (BA1, BS1, BS2, PM2) were adjudicated under the ClinGen HBOPC Expert Panel PALB2 v1.2 CSPEC (doc 1526222356), which specifies gnomAD v4 as the population dataset for BA1/BS1/PM2 and the Fanconi Anemia point tables for BS2; generic ACMG was not needed.
NM_024675.4:c.2970A>T is absent from gnomAD v4.1, gnomAD v2.1 and gnomAD-Canada v1.0 (AF = 0), yielding: BA1 not met (threshold >0.1%), BS1 not met (threshold >0.01%), and PM2 met at Supporting strength (threshold <=0.000333%).
BS2 is not met: no observation of the variant in healthy adults exists in any collected source (ClinVar absent, gnomAD absent and in any case excluded for BS2 per CSPEC, no PMIDs identified), so 0 Fanconi Anemia BS2 points accrue.
No population-frequency, ancestry, homozygote, or disease-prevalence data beyond gnomAD absence were available; no literature was fetched for this variant (paper_extracts and fulltext_map are empty).
No criteria match.
Met · 2
PM2SupportingMet (Supporting): absent from gnomAD v4 (AF=0), satisfying the VCEP frequency threshold of <=1/300,000 (0.000333%).
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Reasoning
The governing ClinGen HBOPC PALB2 v1.2 CSPEC defines PM2 as Frequency <=1/300,000 (0.000333%) in the gnomAD v4 dataset, to be applied as PM2_Supporting (not moderate). The variant is absent from gnomAD v4.1 (no variant record; AF = 0), which satisfies the <=0.000333% threshold, and absence is corroborated by gnomAD v2.1 and gnomAD-Canada v1.0. The CSPEC exception for under-represented sub-populations (n=1 with AF >0.0003%) does not apply because no alleles are present in any population. PM2 is therefore met at Supporting strength.
Rule
PM2_Supporting: Frequency <=1/300,000 (0.000333%) in gnomAD v4 dataset
gnomAD v4.1 (GRCh38) lookup for chr16-23622995-T-A returned no variant record (search_status=absent), i.e., AF = 0, which is <= the 0.000333% PM2 threshold.
Corroborating absence in gnomAD v2.1 (16-23634316-T-A) and gnomAD-Canada v1.0 (HostSeq genomes).
CSPEC PM2 exception (under-represented sub-population with n=1 but frequency >0.0003%) is not applicable because the variant has no alleles in any population.
Still missing
Per-variant gnomAD v4 coverage/filtering metrics (allele number at chr16:23622995) were not included in the case bundle; PM2 assumes adequate sequencing coverage at this site in gnomAD v4.
BP1SupportingMet (Supporting): the VCEP applies BP1 to all missense variants; this is a confirmed missense change (p.Glu990Asp).
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Reasoning
The PALB2 HBOP VCEP (v1.2, cspec) BP1 rule states 'Apply to all missense variants.' at Benign Supporting strength. NM_024675.4:c.2970A>T is a confirmed missense variant (NP_078951.2:p.(Glu990Asp)), so BP1 is met at Supporting strength per the governing framework.
Rule
Apply to all missense variants. (Benign Supporting, PALB2 HBOP VCEP v1.2)
Evidence considered
PALB2 HBOP VCEP v1.2 (cspec) BP1 rule: 'Apply to all missense variants.' with default strength Benign Supporting.
Variant normalization confirms a missense change: NP_078951.2:p.(Glu990Asp) from c.2970A>T; pvs1_variant_assessment consequence_class is 'missense'.
PVS1Not met: missense substitution with no protein length change and no predicted splice impact (SpliceAI max delta 0.026, below the 0.2 threshold).
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Reasoning
Governing framework is the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOC) VCEP specification for PALB2 v1.2 (cspec doc 1526222356), which states PVS1 should be applied 'Use PALB2 PVS1 Decision Tree' with strengths Very Strong through Supporting. The variant NM_024675.4:c.2970A>T is a single-nucleotide missense substitution in exon 9 (NP_078951.2:p.(Glu990Asp)) with no protein length change; it is not a nonsense, frameshift, initiation-codon, canonical +/-1,2 splice, or deletion allele, and the generic PVS1 null-variant buckets are therefore not entered (pvs1_variant_assessment: consequence_class 'missense', variant_bucket 'other', apply_generic_pvs1_framework false). The PALB2 PVS1 decision tree additionally covers predicted/observed splice defects; SpliceAI predicts no significant splice impact (max delta score 0.026, below the VCEP's PP3 threshold of >=0.2), so no splice-defect pathway to PVS1 is triggered. pvs1_gene_context confirms germline loss of function is an established disease mechanism for PALB2 (gene gate 'eligible'), but this gene-level eligibility does not convert a missense allele into a null variant. PVS1 is therefore not met.
Rule
Use PALB2 PVS1 Decision Tree (ClinGen HBOC VCEP PALB2 v1.2)
Evidence considered
Governing framework is the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel (HBOC VCEP) PALB2 v1.2 specification (cspec doc 1526222356), which takes precedence over generic ACMG/AMP for PALB2.
cspec PVS1 rule: 'Use PALB2 PVS1 Decision Tree' (strengths Very Strong/Strong/Moderate/Supporting); the PALB2 decision tree covers null variants (nonsense, frameshift, canonical splice, initiation codon, exonic deletions) and predicted/observed splice defects.
pvs1_variant_assessment.json classifies c.2970A>T as consequence_class 'missense', variant_bucket 'other', canonical_splice_consensus false, apply_generic_pvs1_framework false: the variant does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical +/-1,2 splice consensus variants.
spliceai lookup: max delta score 0.026 (DS_DL 0.026, DS_AG 0.0, DS_AL 0.01, DS_DG 0.001), variant_consequence 'sequence_variant' - no significant predicted splice impact, so the PVS1 splice-defect pathway is not triggered.
pvs1_gene_context.json: germline LoF is an established mechanism for PALB2 (pvs1_gene_gate 'eligible', supporting_sources ['cspec']); gene-level eligibility is necessary but not sufficient - the allele itself is missense and not a null variant.
Mutalyzer/VariantValidator normalization: NM_024675.4 (MANE Select transcript) c.2970A>T maps to exon 9, predicted protein NP_078951.2:p.(Glu990Asp); a single amino-acid substitution with no premature termination and no protein length change.
No PMIDs were identified by the literature pass (literature_pass.json total_pmids = 0) and paper_extracts.json / fulltext_map.json are empty, so no publication-specific evidence was available for the PVS1 evaluation.
Still missing
The full PALB2 PVS1 decision tree / exon map document referenced by cspec is not included in the case bundle (vcep domain_tables empty); this does not change the outcome because the variant is a missense with no predicted splice impact and falls outside every PVS1 decision-tree entry point.
PS1Not met: no predicted splice impact (SpliceAI max delta 0.026), so the VCEP's splicing-based PS1 does not apply.
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Reasoning
Under the PALB2 HBOP VCEP (v1.2, cspec), PS1 is defined via the 'PALB2 PS1 Splicing table' and targets splice-altering variants; this deep-coding missense variant (c.2970A>T, p.Glu990Asp) has no predicted splice impact (SpliceAI max delta 0.026), so the splicing-based PS1 does not apply. Classic PS1 (a different nucleotide change at the same codon producing the same amino acid change, established as pathogenic) is unsupported: the variant is absent from ClinVar, the pm5_candidates artifact reports 0 same-residue candidates, and no literature PMIDs were available. PS1 is therefore not met.
Rule
Use PALB2 PS1 Splicing table (PALB2 HBOP VCEP v1.2)
Evidence considered
PALB2 HBOP VCEP v1.2 (cspec) defines PS1 with the rule 'Use PALB2 PS1 Splicing table'; the criterion is oriented to splice-altering variants rather than classic same-amino-acid-change missense comparators.
SpliceAI lookup for NM_024675.4:c.2970A>T returned max delta score 0.026 (DS_AL 0.01, DS_DL 0.026), indicating no significant predicted splicing impact, so the VCEP splicing-table PS1 does not apply to this variant.
ClinVar search for PALB2 c.2970A>T returned no record; no established pathogenic variant at this position was identified.
pm5_candidates artifact reported total_candidates_seen 0 and same_residue_candidates 0, providing no comparator variant for classic PS1 evaluation.
Still missing
No targeted search for alternate alleles at c.2970 (e.g., c.2970A>C, which would also predict p.Glu990Asp) or for any PALB2 p.Glu990 variants in ClinVar/LOVD was performed; ClinVar was queried only for the exact c.2970A>T allele.
PP3Not met: SpliceAI max delta 0.026 is below the VCEP's 0.2 threshold, and missense in-silico predictors are barred for PP3.
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Reasoning
Variant NM_024675.4:c.2970A>T is a missense change (p.Glu990Asp) in PALB2. The governing PALB2 VCEP v1.2 (cspec doc 1526222356) PP3 rule has two parts: (1) 'Missense: Do not use' — missense in-silico protein predictors (REVEL/BayesDel/aGVGD) are explicitly barred for PP3; (2) the splicing path applies to 'silent, missense/in-frame and intronic variants outside of donor and acceptor 1,2 sites' with SpliceAI >= 0.2. Because the variant is missense/in-frame, the splice-based PP3 path IS evaluable: SpliceAI reports max delta score 0.026 (DS_DL 0.026, DS_AL 0.01, DS_AG 0.0, DS_DG 0.001), far below the VCEP PP3 threshold of 0.2, so PP3 is not met. REVEL (0.014) and BayesDel (-0.568457) were retrieved but are not applied because the VCEP bars missense in-silico tools for PP3; BayesDel additionally has no verified published threshold.
Rule
PALB2 VCEP v1.2 PP3 (supporting): splice-based PP3 for silent, missense/in-frame, and intronic variants outside donor/acceptor 1,2 sites with SpliceAI ≥0.2; missense in-silico tools not used.
Evidence considered
Governing framework is the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 VCEP v1.2 (cspec). PP3 rule text: '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.'
SpliceAI lookup for NM_024675.4:c.2970A>T returns max delta score 0.026 (DS_AG 0.0, DS_AL 0.01, DS_DG 0.001, DS_DL 0.026), which is below the VCEP PP3 splice threshold of ≥0.2, so splice-based PP3 is not met.
REVEL score 0.014 and BayesDel score -0.568457 were retrieved from local predictor lookups but are not applied to PP3 because the PALB2 VCEP explicitly states 'Missense: Do not use' for PP3; BayesDel also lacks a verified published threshold (no named publication/table available).
Still missing
No RNA-based splicing assay data are available for this variant; SpliceAI in-silico prediction only. Absence of RNA data does not change the not_met call because the in-silico score is far below the VCEP threshold.
BA1Not met: absent from gnomAD v4 (AF=0), below the VCEP BA1 threshold of >0.1%.
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Reasoning
Governing framework is the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 Specification v1.2 (CSPEC doc 1526222356), which defines BA1 as Grpmax Filtering AF >0.1% in the gnomAD v4 dataset. NM_024675.4:c.2970A>T (chr16:23622995T>A, GRCh38) is absent from gnomAD v4.1 (no variant record; AF = 0) and is also absent from gnomAD v2.1 and gnomAD-Canada v1.0. An AF of 0 does not exceed the 0.1% threshold, so BA1 (Stand Alone) is not met.
Rule
BA1: Grpmax Filtering AF >0.1% in gnomAD v4 dataset (Stand Alone)
Evidence considered
ClinGen HBOPC VCEP PALB2 v1.2 CSPEC BA1 rule: 'Grpmax Filtering AF >.1% in gnomAD v4 dataset' (Stand Alone).
gnomAD v4.1 (GRCh38) lookup for chr16-23622995-T-A returned no variant record (search_status=absent), i.e., AF = 0.
Corroborating absence in gnomAD v2.1 (16-23634316-T-A) and gnomAD-Canada v1.0 (HostSeq genomes).
Still missing
Per-variant gnomAD v4 coverage/filtering metrics (allele number at chr16:23622995) were not included in the case bundle; the absence of a variant record was taken at face value.
BS1Not met: absent from gnomAD v4 (AF=0), below the VCEP BS1 threshold of >0.01%.
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Reasoning
Under the governing ClinGen HBOPC PALB2 v1.2 CSPEC, BS1 requires Grpmax Filtering AF >0.01% in the gnomAD v4 dataset. The variant is absent from gnomAD v4.1 (AF = 0), and also from gnomAD v2.1 and gnomAD-Canada v1.0. AF 0 does not exceed the 0.01% threshold, so BS1 (Strong) is not met.
Rule
BS1: Grpmax Filtering AF >0.01% in gnomAD v4 dataset (Strong)
Evidence considered
ClinGen HBOPC VCEP PALB2 v1.2 CSPEC BS1 rule: 'Grpmax Filtering AF >.01% in gnomAD v4 dataset' (Strong).
gnomAD v4.1 (GRCh38) lookup for chr16-23622995-T-A returned no variant record (search_status=absent), i.e., AF = 0.
Corroborating absence in gnomAD v2.1 (16-23634316-T-A) and gnomAD-Canada v1.0 (HostSeq genomes).
Still missing
Per-variant gnomAD v4 coverage/filtering metrics (allele number at chr16:23622995) were not included in the case bundle.
BS2Not met: no observed instances in healthy adults, so 0 BS2 points accrued (>=4 required for Strong).
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Reasoning
The governing ClinGen HBOPC PALB2 v1.2 CSPEC assigns BS2 via the Fanconi Anemia BS2 point tables (BS2 >=4 points = Strong; BS2_Moderate = 2 points; BS2_Supporting = 1 point) based on observed instances of the variant in healthy adults, and explicitly states 'Do not use for individuals in population based cohorts, such as gnomAD'. The case bundle contains no observations of c.2970A>T in any healthy adult: the variant is absent from ClinVar, absent from gnomAD (which is in any case excluded for BS2), and no literature was identified (literature_pass total_pmids = 0). With zero observed instances, 0 points accrue, so BS2 is not met.
Rule
BS2: >=4 points (Strong) / 2 points (Moderate) / 1 point (Supporting) per Fanconi Anemia BS2 tables; population cohorts such as gnomAD excluded
Evidence considered
ClinGen HBOPC VCEP PALB2 v1.2 CSPEC BS2 rule: point-based per Fanconi Anemia BS2 tables (BS2 >=4 points Strong; BS2_Moderate = 2 points; BS2_Supporting = 1 point); instructions state 'Do not use for individuals in population based cohorts, such as gnomAD'.
ClinVar search for PALB2 c.2970A>T returned no submissions (variant absent), so no reported healthy-adult observations exist in ClinVar.
gnomAD v4.1, gnomAD v2.1 and gnomAD-Canada v1.0 all report the variant absent; per CSPEC, population cohorts are not a valid BS2 source regardless.
literature_pass.json reports total_pmids = 0, so no paper-based healthy-adult observations were available.
Still missing
The Fanconi Anemia BS2 point tables referenced by the CSPEC are not included in the case bundle (vcep_materials.domain_tables is empty), so the exact per-instance point values could not be applied.
No curated case-level or literature-based observations of this variant in healthy adults (or co-occurrence instances) were available to score.
PS4Not assessed: no case-control or prevalence data existed to evaluate enrichment (threshold OR >=3, p <=0.05).
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Reasoning
PS4 is Applicable under the governing ClinGen HBOC VCEP PALB2 v1.2 specification, which requires case-control enrichment evidence: p-value <= 0.05 AND (odds ratio, hazard ratio, or relative risk >= 3 OR lower 95% CI >= 1.5) at Strong strength. PS4_Moderate (proband counting) is explicitly not for use in this VCEP. No case-control study or variant-specific prevalence data for c.2970A>T (p.Glu990Asp) could be identified: the literature pass returned 0 PMIDs, paper_extracts.json and fulltext_map.json are empty, and no proband counts or enrichment statistics appear anywhere in the case evidence. With no enrichment data at all, the criterion cannot be evaluated, so it is recorded as not_assessed rather than met.
Rule
Case-control studies; p-value <= .05 AND (Odds ratio, hazard ratio, or relative risk >= 3 OR lower 95% CI >= 1.5). Strong only; PS4_Moderate: Do not use (PALB2 VCEP v1.2).
Evidence considered
The ClinGen HBOC VCEP PALB2 v1.2 specification (cspec doc 1526222356) defines PS4 as Applicable with a single Strong strength rule: 'Case-control studies; p-value <= .05 AND (Odds ratio, hazard ratio, or relative risk >= 3 OR lower 95% CI >= 1.5)'.
The same specification states 'PS4_Moderate: Do not use. Proband counting for genes causing a common disorder need to be calibrated in a population-specific way before use', so proband-only counting cannot substitute for a case-control study.
literature_pass.json reports total_pmids: 0 with the note 'No PMIDs found across evidence sources', and paper_extracts.json / fulltext_map.json are empty, so no case-control or prevalence evidence for this variant is available to the pipeline.
Still missing
No case-control study (or any variant-specific prevalence/enrichment data) for PALB2 c.2970A>T was identified; literature_pass found 0 PMIDs and no full texts were fetched.
If human review can locate PALB2 case-control series (e.g., breast/ovarian/pancreatic cancer cohorts), PS4 could be scored against the VCEP threshold (p<=0.05 AND OR/HR/RR >=3 OR lower 95% CI >=1.5).
PM3Not assessed: no proband, allele, or phase observations existed, so no Fanconi anemia PM3 points could be assigned.
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Reasoning
The governing PALB2 VCEP v1.2 specification (cspec) defines PM3 as a points-per-proband criterion using the Fanconi Anemia PM3 tables (PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong >= 4 points, PM3_VeryStrong >= 8 points), applicable to the autosomal recessive Fanconi anemia complementation group N context; v1.2 release notes clarify when to assume variants are in trans. The case bundle contains no proband-level data at all: no affected individual reported carrying c.2970A>T, no second PALB2 variant, no trans/cis phase determination, no family segregation data, and no published or ClinVar observations (ClinVar search returned no records; literature_pass found 0 PMIDs; paper_extracts.json and fulltext_map.json are empty). With zero allele/phase observations, no PM3 points can be assigned and the criterion cannot be adjudicated.
Rule
PM3 (PALB2 VCEP v1.2): points per proband per Fanconi Anemia PM3 tables - PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong >= 4 points, PM3_VeryStrong >= 8 points; requires variant in trans with a pathogenic variant in an affected (biallelic) proband
Evidence considered
PALB2 VCEP v1.2 (cspec) PM3 rule: points per proband per the Fanconi Anemia PM3 tables; PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong >= 4 points, PM3_VeryStrong >= 8 points; v1.2 release notes state 'Clarified when to assume in trans for PM3'
ClinVar search for PALB2 c.2970A>T returned no records (evidence_sentence: 'This variant is absent from ClinVar.'), so ClinVar reports no allele or phase observations for this variant
literature_pass.json reports total_pmids = 0 with empty high/medium priority paper lists and an empty criteria_index ('No PMIDs found across evidence sources'), and paper_extracts.json/fulltext_map.json are both empty, so no published proband observations of this variant are available
case_summary.json contains no proband phenotype, genotype, family segregation, or phase data for this variant; only variant-level annotations are present
No second PALB2 variant or biallelic state is documented anywhere in the case bundle, so PM3 points cannot be assigned
Still missing
No proband/affected-individual observations of c.2970A>T: the case bundle contains only variant-level annotations (population frequency, in silico predictors, cancer databases), with no case-level genotype or phenotype data
No information on a second PALB2 variant or on trans/cis phase for any carrier, which PM3 requires for the recessive (Fanconi anemia complementation group N) context
No literature or ClinVar entries reporting this variant in any biallelic or monoallelic carrier, so no external allele observations exist to score
PP1Not assessed: no pedigree, LOD, or segregation data existed (Supporting requires LOD >=0.3), pending family studies.
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Reasoning
PP1 is applicable under the PALB2 VCEP v1.2, which mandates quantitative co-segregation analysis: 'Quantitative co-segregation analysis is mandated for more accurate assessment of causality for PALB2 alterations.' Thresholds: AD condition PP1_Supporting LOD >=0.3 or Bayes factor LR >=2:1; PP1_Moderate LOD >=0.60 or LR >=4:1; PP1_Strong LOD >=1.26 or LR >=18:1; AR condition segregation in 1, 2, or >=3 affected relatives (supporting/moderate/strong). No proband, pedigree, affected-relative genotype, LOD, or Bayes-factor data exist anywhere in this case bundle: the variant is absent from ClinVar, literature_pass.json reports 0 PMIDs across all evidence sources, and fulltext_map.json/paper_extracts.json are empty. With no segregation observations of any kind, PP1 cannot be met or refuted and is therefore not_assessed pending family data.
Rule
PP1 (PALB2 VCEP v1.2): AD LOD >=0.3 or LR >=2:1 (Supporting); LOD >=0.60 or LR >=4:1 (Moderate); LOD >=1.26 or LR >=18:1 (Strong); AR segregation in 1/2/>=3 affected relatives.
Evidence considered
cspec PALB2 v1.2 PP1 rule (AD condition): LOD >=1.26 or LR >=18:1 (Strong), LOD >=0.60 or LR >=4:1 (Moderate), LOD >=0.3 or LR >=2:1 (Supporting); AR condition: segregation in >=3, 2, or 1 affected relatives respectively.
ClinVar was searched for NM_024675.4:c.2970A>T (and PALB2 c.2970A>T, genomic equivalents) and returned no entry (evidence.json clinvar result found=false), so no curated co-segregation observations are available from ClinVar.
literature_pass.json reports total_pmids 0 ('No PMIDs found across evidence sources'); fulltext_map.json and paper_extracts.json are empty, so no published family/segregation data was available to review for this variant.
Still missing
No pedigree/family segregation data for this variant: no genotypes of affected relatives, no LOD score or Bayes factor (LR), and no meioses information from which to compute quantitative co-segregation per the PALB2 VCEP PP1 rule.
BS4Not assessed: no pedigree or segregation data existed to test lack of segregation (LOD <=-0.32 at Supporting).
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Reasoning
BS4 is applicable under the PALB2 VCEP v1.2 and requires quantitative evidence of lack of segregation: BS4_Supporting LOD <= -0.32 or LR <=0.48; BS4_Moderate LOD <= -0.64 or LR <=0.23; BS4 LOD <= -1.28 or LR <=0.053:1. The case bundle contains no non-segregation evidence whatsoever: there is no pedigree, no affected family members tested (carrier or non-carrier), no meioses, and no LOD/Bayes-factor calculation; the variant is absent from ClinVar and no relevant literature was retrieved (0 PMIDs). Lack of segregation can therefore be neither demonstrated nor refuted, so BS4 is not_assessed pending family data.
Rule
BS4 (PALB2 VCEP v1.2): LOD <= -0.32 or LR <=0.48 (Supporting); LOD <= -0.64 or LR <=0.23 (Moderate); LOD <= -1.28 or LR <=0.053:1 (Strong).
Evidence considered
cspec PALB2 v1.2 BS4 strength rules: Strong LOD <= -1.28 or LR <=0.053:1; Moderate LOD <= -0.64 or LR <=0.23; Supporting LOD <= -0.32 or LR <=0.48; originalACMGSummary 'Lack of segregation in affected members of a family.'
ClinVar was searched for NM_024675.4:c.2970A>T and returned no entry, so no curated observations of non-segregation (or segregation) are available from ClinVar.
literature_pass.json reports total_pmids 0 and fulltext_map.json/paper_extracts.json are empty, so no published family studies reporting lack of segregation for this variant were available to review.
Still missing
No non-segregation/family data: no affected relatives tested and found not to carry the variant, and no LOD score or Bayes factor (LR) from which BS4 could be evaluated.
Not applicable · 16· recorded as not applicableShow reasons ▾Hide reasons ▴PS2VCEPNot applicable: the PALB2 VCEP bars PS2 because informative de novo occurrences have not been observed for this disease.
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Reasoning
The governing ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOPC) VCEP specification for PALB2 (v1.2, cspec doc 1526222356) explicitly marks PS2 as Not Applicable: '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.' 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 occurs as an apparently sporadic event, de novo is unlikely to ever be informative. Under framework precedence, generic ACMG PS2 must not be applied for this gene/disease, so the criterion is not_applicable regardless of the absence of proband parental-testing data in this case bundle.
VCEP rule
PS2 not applicable per PALB2 VCEP v1.2 (cspec): 'Do not use for AD or AR disease' (no informative de novo occurrences observed for PALB2; de novo unlikely to be informative for PALB2-related cancer predisposition).
Evidence considered
cspec PALB2 v1.2 PS2 entry (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'; AD clause: 'Autosomal Dominant Disease: Do not use-Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified.'
The PALB2 VCEP v1.2 is the applicable governing specification (precedence rank 1, framework_mode criteria_combination), so its PS2 applicability determination supersedes generic ACMG/AMP PS2 for this case.
PS3VCEPNot applicable: the PALB2 VCEP does not use PS3, and no variant-specific functional assay data were available.
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Reasoning
The governing framework is the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel (HBOP) VCEP specification for PALB2 v1.2 (cspec, precedence rank 1), which explicitly declares PS3 'Not Applicable'. Functional assay evidence therefore is not scored as a criterion in this framework. Independently, the case bundle contains no variant-specific functional data for NM_024675.4:c.2970A>T (p.Glu990Asp): literature_pass.json reports 0 PMIDs, paper_extracts.json and fulltext_map.json are empty, and OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence (not_reviewed=true, is_variant_specific=false).
Evidence considered
The governing ClinGen HBOP VCEP PALB2 specification v1.2 (cspec) explicitly marks PS3 as 'Not Applicable', so functional assay evidence is not a scored criterion in this framework.
The case evidence bundle contains no functional assay evidence for c.2970A>T: literature_pass.json lists 0 PMIDs ('No PMIDs found across evidence sources'), paper_extracts.json is empty, and fulltext_map.json is empty.
OncoKB lists PALB2 E990D as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence (not_reviewed=true, is_variant_specific=false), confirming absence of curated variant-specific functional data.
No in vitro or in vivo functional study of this exact variant (c.2970A>T / p.Glu990Asp) was identified in any evidence source in the bundle.
Still missing
No validated functional assay data (e.g., homologous recombination / DNA repair functional assay) exist for PALB2 c.2970A>T (p.Glu990Asp) in the evidence bundle; the governing VCEP declares PS3 not applicable, so this gap does not affect the framework-based classification.
PM1VCEPNot applicable: the PALB2 VCEP does not use PM1; no VCEP-approved critical domain list exists for this gene.
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Reasoning
The PALB2 HBOP VCEP (v1.2, cspec) declares PM1 'Not Applicable' for PALB2. The vcep_materials.json domain_tables key is empty ({}) for this gene, so there is no VCEP-approved critical functional domain list against which to check residue Glu990. Per the governing framework, PM1 is not used in this case.
VCEP rule
PM1: Not Applicable (PALB2 HBOP VCEP v1.2)
Evidence considered
PALB2 HBOP VCEP v1.2 (cspec) lists PM1 applicability as 'Not Applicable', so PM1 is not scored in this framework.
vcep_materials.json domain_tables is empty ({}) for PALB2, meaning no authoritative VCEP domain table exists to check residue Glu990 against.
PM4VCEPNot applicable: the variant is missense, not an in-frame indel or stop-loss, the only allele classes the VCEP considers under PM4.
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Reasoning
The governing HBOC VCEP PALB2 v1.2 specification (cspec) marks PM4 as 'Not applicable' with the instruction: 'Do not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only.' The variant NM_024675.4:c.2970A>T is a missense substitution (p.(Glu990Asp)) that produces no protein length change whatsoever - it is neither an in-frame insertion/deletion nor a stop-loss variant, the only two allele classes the VCEP would ever consider under PM4. PM4 is therefore not applicable under the governing VCEP framework; no generic ACMG fallback is used because a gene-specific specification exists.
VCEP rule
PM4: Not applicable - do not use for in-frame insertions/deletions less than a single exon; use for stop-loss variants only (ClinGen HBOC VCEP PALB2 v1.2)
Evidence considered
cspec PM4 entry: applicability 'Not applicable'; instructionsToUse 'Do not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only.'
VariantValidator predicted protein consequence NP_078951.2:p.(Glu990Asp) confirms a single amino-acid substitution; no in-frame indel and no stop-loss effect, so the variant class is outside the only PM4-eligible allele types defined by the VCEP.
Per instructions, the gene-specific HBOC VCEP specification governs; generic ACMG/AMP PM4 is not applied.
PM5N/ANot applicable: the VCEP limits PM5 to truncating variants upstream of p.Tyr1183; this missense does not qualify.
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Reasoning
The PALB2 HBOP VCEP (v1.2, cspec) redefines PM5 as a truncation-cutoff rule: it applies to frameshifting/truncating variants with premature termination codons upstream of p.Tyr1183 and to NMD-prone splice variants qualifying for PVS1_VS(RNA) - not to classic same-residue missense changes. This variant is a missense (p.Glu990Asp), so the VCEP PM5 rule does not apply. The pm5_candidates artifact independently reports classic PM5 search as not eligible (pm5_mode truncation_cutoff_gene_specific, eligible_for_classic_pm5_search false, recommendation not_applicable, 0 same-residue candidates).
Rule
Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183 (PALB2 HBOP VCEP v1.2)
Evidence considered
PALB2 HBOP VCEP v1.2 (cspec) PM5 rule text: 'Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183. Apply to splice variants as with premature termination codons upstream of p.Tyr1183 where PVS1_VS(RNA) is applied...'; p.Glu990Asp is neither frameshifting/truncating nor splice-altering.
PM6VCEPNot applicable: the PALB2 VCEP bars PM6 because informative de novo occurrences have not been observed for this disease.
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Reasoning
The governing ClinGen HBOPC VCEP specification for PALB2 (v1.2, cspec doc 1526222356) explicitly marks PM6 as Not Applicable with identical reasoning to PS2: '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 further notes that in a biallelic (Fanconi anemia) state de novo occurrences are too rare to be informative and are exceedingly unlikely to be confirmed as in trans without long-range technologies. Under framework precedence, generic ACMG PM6 must not be applied for this gene/disease, so the criterion is not_applicable.
VCEP rule
PM6 not applicable per PALB2 VCEP v1.2 (cspec): 'Do not use for AD or AR disease'.
Evidence considered
cspec PALB2 v1.2 PM6 entry (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'.
The PALB2 VCEP v1.2 is the applicable governing specification (precedence rank 1), so its PM6 applicability determination supersedes generic ACMG/AMP PM6 for this case.
PP4VCEPNot applicable: the PALB2 VCEP does not use PP4 because the phenotype is not specific to a single genetic etiology.
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Reasoning
PP4 is marked Not Applicable by the governing ClinGen HBOC VCEP PALB2 v1.2 specification: for an autosomal-dominant disorder such as PALB2-associated breast cancer, the phenotype is not specific for a single genetic etiology (genetic heterogeneity; no features readily distinguish hereditary from sporadic causes), and the VCEP directs phenotype considerations for the AR (Fanconi anemia) context to PM3 instead. The case also contains no proband phenotype or family-history data that could be evaluated, so PP4 cannot contribute evidence regardless.
VCEP rule
Not Applicable per PALB2 VCEP v1.2 (genetic heterogeneity of breast cancer; phenotype not specific for a single genetic etiology).
Evidence considered
The ClinGen HBOC VCEP PALB2 v1.2 specification marks PP4 as 'Not applicable' with the instruction: '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'.
Still missing
No proband phenotype or family-history data are present in the case bundle; under the PALB2 VCEP this would not change the outcome, as PP4 is Not Applicable.
PP5VCEPNot applicable: the PALB2 VCEP does not use PP5, and ClinVar has no expert-panel classification for this variant.
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Reasoning
PP5 is marked 'Not Applicable for this VCEP' by the governing ClinGen HBOC VCEP PALB2 v1.2 specification, per the ClinGen SVI VCEP Review Committee recommendation that this criterion not be used. Independently of the framework, PP5 requires an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic, and ClinVar has no entry at all for PALB2 c.2970A>T (variant absent, zero submissions), so no expert-panel assertion exists that could trigger PP5.
VCEP rule
Not Applicable per PALB2 VCEP v1.2 (criterion not for use per ClinGen SVI VCEP Review Committee); additionally no exact-variant ClinVar expert-panel classification exists.
Evidence considered
The ClinGen HBOC VCEP PALB2 v1.2 specification marks PP5 as 'Not Applicable for this VCEP' with the instruction 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee'.
ClinVar search for PALB2 c.2970A>T returned no result ('This variant is absent from ClinVar'), so no expert-panel (or any) ClinVar classification exists for this exact variant to support PP5.
Still missing
If a future ClinVar expert-panel (e.g., ClinGen HBOC VCEP) classification of this exact variant becomes available, PP5 status should be revisited; currently the variant is absent from ClinVar.
BS3VCEPNot applicable: the PALB2 VCEP does not use BS3, and no assay demonstrating normal protein function was available.
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Reasoning
The governing ClinGen HBOP VCEP PALB2 v1.2 specification (cspec, precedence rank 1) explicitly declares BS3 'Not Applicable', so lack-of-deleterious-effect functional assay evidence is not a scored criterion in this framework. Independently, no assay demonstrating normal protein function for NM_024675.4:c.2970A>T (p.Glu990Asp) exists in the case bundle: no PMIDs were collected, paper_extracts.json and fulltext_map.json are empty, and OncoKB has no variant-specific functional evidence. Therefore BS3 cannot be met under any framework.
Evidence considered
The governing ClinGen HBOP VCEP PALB2 specification v1.2 (cspec) explicitly marks BS3 as 'Not Applicable', so lack-of-deleterious-effect functional assay evidence is not a scored criterion in this framework.
The case evidence bundle contains no assay data showing normal function for c.2970A>T: literature_pass.json lists 0 PMIDs, paper_extracts.json is empty, and fulltext_map.json is empty.
OncoKB reports no variant-specific reviewed functional evidence for PALB2 E990D (classification 'Unknown Oncogenic Effect'), so no curated source supports normal function for this variant.
No functional assay (e.g., homologous recombination complementation or protein-interaction assay) testing this exact variant was identified in any evidence source in the bundle.
Still missing
No functional assay evidence demonstrating normal/benign function for PALB2 c.2970A>T (p.Glu990Asp) exists in the evidence bundle; the governing VCEP declares BS3 not applicable, so this gap does not affect the framework-based classification.
BP2VCEPNot applicable: the PALB2 VCEP does not use BP2.
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Reasoning
The governing PALB2 VCEP v1.2 specification (cspec) explicitly lists BP2 with applicability 'Not Applicable'. The gene-specific framework takes precedence over generic ACMG/AMP, so generic BP2 (variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis for a recessive disorder) is not applied in this framework and is not evaluated here.
VCEP rule
BP2: Not Applicable per PALB2 VCEP v1.2 (cspec applicability declaration)
Evidence considered
PALB2 VCEP v1.2 (cspec) marks BP2 as 'Not Applicable' in its criteria table, so the generic ACMG/AMP BP2 criterion is superseded by the gene-specific specification
BP3VCEPNot applicable: the variant is missense, not an in-frame deletion, and PALB2 has no repetitive regions of unknown function.
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Reasoning
The governing HBOC VCEP PALB2 v1.2 specification (cspec) marks BP3 as 'Not applicable' with the instruction: 'Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function.' The variant NM_024675.4:c.2970A>T is a missense substitution (p.(Glu990Asp)), not an in-frame deletion/insertion, and PALB2 is not considered to contain repetitive regions without known function per the VCEP. BP3 is therefore not applicable under the governing VCEP framework; no generic ACMG fallback is used because a gene-specific specification exists.
VCEP rule
BP3: Not applicable - small in-frame losses not confirmed/refuted as mechanism for PALB2; PALB2 not considered to have repetitive regions without known function (ClinGen HBOC VCEP PALB2 v1.2)
Evidence considered
cspec BP3 entry: applicability 'Not applicable'; instructionsToUse 'Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function.'
VariantValidator predicted protein consequence NP_078951.2:p.(Glu990Asp) confirms the allele is a missense substitution, not an in-frame indel in a repetitive region, so BP3's trigger (in-frame indel in a functionally unknown repeat region) is absent.
Per instructions, the gene-specific HBOC VCEP specification governs; generic ACMG/AMP BP3 is not applied.
BP4N/ANot applicable: the VCEP bars BP4 for missense variants, even though SpliceAI 0.026 would satisfy the splice threshold.
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Reasoning
The governing PALB2 VCEP v1.2 BP4 rule states: 'Missense: Do not use. Splicing: No predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.' c.2970A>T is a missense variant (p.Glu990Asp), and the VCEP explicitly bars BP4 for missense variants across both sub-paths (missense in-silico and splice). Although SpliceAI max delta 0.026 is ≤0.1 and would nominally satisfy the splice-based BP4 threshold, the VCEP's 'Do not apply for missense variants' instruction takes precedence: a low SpliceAI score cannot serve as benign-supporting evidence for a missense variant because it does not exclude a protein-level effect. BP4 is therefore not applicable under the governing framework.
Rule
PALB2 VCEP v1.2 BP4 (supporting): splice-based BP4 when SpliceAI ≤0.1; explicitly 'Do not apply for missense variants'.
Evidence considered
Governing framework is the ClinGen HBOC EP PALB2 VCEP v1.2 (cspec). BP4 rule text: 'Missense: Do not use. Splicing: No predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.'
SpliceAI lookup for NM_024675.4:c.2970A>T returns max delta score 0.026, which would nominally meet the ≤0.1 splice threshold, but the VCEP explicitly states BP4 'Do not apply for missense variants'; the variant is missense (p.Glu990Asp), so BP4 is not applied.
REVEL (0.014) and BayesDel (-0.568457) were retrieved but are not applied, consistent with the VCEP missense exclusion for BP4; BayesDel also has no verified published threshold.
Still missing
No functional/RNA assay data are available, but this does not affect applicability: the VCEP missense exclusion applies regardless of RNA evidence.
BP5VCEPNot applicable: the PALB2 VCEP does not use BP5 because PALB2's moderate penetrance allows frequent co-occurrence.
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Reasoning
BP5 is marked Not Applicable by the governing ClinGen HBOC VCEP PALB2 v1.2 specification: the VCEP instructs that the criterion not be used because cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and PALB2 has moderate penetrance so it will naturally co-occur with other pathogenic variants more frequently. The case evidence contains no alternative-molecular-basis information either, so BP5 cannot apply.
VCEP rule
Not Applicable per PALB2 VCEP v1.2 (co-occurrence with an alternate molecular basis is not informative for PALB2).
Evidence considered
The ClinGen HBOC VCEP PALB2 v1.2 specification marks BP5 as 'Not applicable' with the instruction: '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.'
BP6VCEPNot applicable: the PALB2 VCEP does not use BP6, and ClinVar has no expert-panel classification for this variant.
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Reasoning
BP6 is marked 'Not Applicable for this VCEP' by the governing ClinGen HBOC VCEP PALB2 v1.2 specification, per the ClinGen SVI VCEP Review Committee recommendation that this criterion not be used. Independently of the framework, BP6 requires an exact-variant ClinVar expert-panel classification of Benign/Likely benign, and ClinVar has no entry at all for PALB2 c.2970A>T (variant absent, zero submissions), so no expert-panel assertion exists that could trigger BP6.
VCEP rule
Not Applicable per PALB2 VCEP v1.2 (criterion not for use per ClinGen SVI VCEP Review Committee); additionally no exact-variant ClinVar expert-panel classification exists.
Evidence considered
The ClinGen HBOC VCEP PALB2 v1.2 specification marks BP6 as 'Not Applicable for this VCEP' with the instruction 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee'.
ClinVar search for PALB2 c.2970A>T returned no result ('This variant is absent from ClinVar'), so no expert-panel (or any) ClinVar classification exists for this exact variant to support BP6.
Still missing
If a future ClinVar expert-panel classification of this exact variant as Benign/Likely benign becomes available, BP6 status should be revisited; currently the variant is absent from ClinVar.
BP7N/ANot applicable: the variant is missense, not synonymous or deep intronic, the allele classes BP7 covers.
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Reasoning
The governing PALB2 VCEP v1.2 BP7 rule applies to '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', with BP7(RNA) variants (observed lack of aberrant RNA defect) available at higher weights. c.2970A>T is a missense substitution (p.Glu990Asp) in the coding sequence, not a synonymous or deep intronic variant, so BP7 does not apply. Additionally, no RNA assay evidence exists in this case for the BP7(RNA) path.
Rule
PALB2 VCEP v1.2 BP7 (supporting): synonymous and deep intronic variants (>+7 donor / >-21 acceptor); BP7(RNA) for observed lack of aberrant RNA defect in silent and intronic variants.
Evidence considered
Governing framework is the ClinGen HBOC EP PALB2 VCEP v1.2 (cspec). BP7 rule text: '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.'
The variant is a missense substitution (p.Glu990Asp), which falls outside the BP7 scope of synonymous and deep intronic variants; no RNA assay evidence is present in the case bundle.
Still missing
No RNA assay data are available (BP7_Strong(RNA)/BP7_Moderate(RNA) paths cannot be evaluated), though BP7 is not applicable regardless because the variant is missense rather than synonymous/deep intronic.
Every interpreted variant in PALB2, mapped onto the exon structure of NM_024675.4. Select a row to find it on the plot.
PALB2NM_024675.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PALB2—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat +135 bp
0.010
SpliceAI acceptor gainat +1 bp
0.000
SpliceAI donor lossat -26 bp
0.026
SpliceAI donor gainat -227 bp
0.001
Pangolin splice lossmagnitude shown
-0.001
Pangolin splice gain
0.001
Other predictors
REVEL
0.014
BayesDel
-0.568
How the predictions were used
PP3Not met: SpliceAI max delta 0.026 is below the VCEP's 0.2 threshold, and missense in-silico predictors are barred for PP3.
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Reasoning
Variant NM_024675.4:c.2970A>T is a missense change (p.Glu990Asp) in PALB2. The governing PALB2 VCEP v1.2 (cspec doc 1526222356) PP3 rule has two parts: (1) 'Missense: Do not use' — missense in-silico protein predictors (REVEL/BayesDel/aGVGD) are explicitly barred for PP3; (2) the splicing path applies to 'silent, missense/in-frame and intronic variants outside of donor and acceptor 1,2 sites' with SpliceAI >= 0.2. Because the variant is missense/in-frame, the splice-based PP3 path IS evaluable: SpliceAI reports max delta score 0.026 (DS_DL 0.026, DS_AL 0.01, DS_AG 0.0, DS_DG 0.001), far below the VCEP PP3 threshold of 0.2, so PP3 is not met. REVEL (0.014) and BayesDel (-0.568457) were retrieved but are not applied because the VCEP bars missense in-silico tools for PP3; BayesDel additionally has no verified published threshold.
Rule
PALB2 VCEP v1.2 PP3 (supporting): splice-based PP3 for silent, missense/in-frame, and intronic variants outside donor/acceptor 1,2 sites with SpliceAI ≥0.2; missense in-silico tools not used.
Evidence considered
Governing framework is the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 VCEP v1.2 (cspec). PP3 rule text: '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.'
SpliceAI lookup for NM_024675.4:c.2970A>T returns max delta score 0.026 (DS_AG 0.0, DS_AL 0.01, DS_DG 0.001, DS_DL 0.026), which is below the VCEP PP3 splice threshold of ≥0.2, so splice-based PP3 is not met.
REVEL score 0.014 and BayesDel score -0.568457 were retrieved from local predictor lookups but are not applied to PP3 because the PALB2 VCEP explicitly states 'Missense: Do not use' for PP3; BayesDel also lacks a verified published threshold (no named publication/table available).
Still missing
No RNA-based splicing assay data are available for this variant; SpliceAI in-silico prediction only. Absence of RNA data does not change the not_met call because the in-silico score is far below the VCEP threshold.
BP4N/ANot applicable: the VCEP bars BP4 for missense variants, even though SpliceAI 0.026 would satisfy the splice threshold.
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Reasoning
The governing PALB2 VCEP v1.2 BP4 rule states: 'Missense: Do not use. Splicing: No predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.' c.2970A>T is a missense variant (p.Glu990Asp), and the VCEP explicitly bars BP4 for missense variants across both sub-paths (missense in-silico and splice). Although SpliceAI max delta 0.026 is ≤0.1 and would nominally satisfy the splice-based BP4 threshold, the VCEP's 'Do not apply for missense variants' instruction takes precedence: a low SpliceAI score cannot serve as benign-supporting evidence for a missense variant because it does not exclude a protein-level effect. BP4 is therefore not applicable under the governing framework.
Rule
PALB2 VCEP v1.2 BP4 (supporting): splice-based BP4 when SpliceAI ≤0.1; explicitly 'Do not apply for missense variants'.
Evidence considered
Governing framework is the ClinGen HBOC EP PALB2 VCEP v1.2 (cspec). BP4 rule text: 'Missense: Do not use. Splicing: No predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.'
SpliceAI lookup for NM_024675.4:c.2970A>T returns max delta score 0.026, which would nominally meet the ≤0.1 splice threshold, but the VCEP explicitly states BP4 'Do not apply for missense variants'; the variant is missense (p.Glu990Asp), so BP4 is not applied.
REVEL (0.014) and BayesDel (-0.568457) were retrieved but are not applied, consistent with the VCEP missense exclusion for BP4; BayesDel also has no verified published threshold.
Still missing
No functional/RNA assay data are available, but this does not affect applicability: the VCEP missense exclusion applies regardless of RNA evidence.
BP7N/ANot applicable: the variant is missense, not synonymous or deep intronic, the allele classes BP7 covers.
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Reasoning
The governing PALB2 VCEP v1.2 BP7 rule applies to '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', with BP7(RNA) variants (observed lack of aberrant RNA defect) available at higher weights. c.2970A>T is a missense substitution (p.Glu990Asp) in the coding sequence, not a synonymous or deep intronic variant, so BP7 does not apply. Additionally, no RNA assay evidence exists in this case for the BP7(RNA) path.
Rule
PALB2 VCEP v1.2 BP7 (supporting): synonymous and deep intronic variants (>+7 donor / >-21 acceptor); BP7(RNA) for observed lack of aberrant RNA defect in silent and intronic variants.
Evidence considered
Governing framework is the ClinGen HBOC EP PALB2 VCEP v1.2 (cspec). BP7 rule text: '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.'
The variant is a missense substitution (p.Glu990Asp), which falls outside the BP7 scope of synonymous and deep intronic variants; no RNA assay evidence is present in the case bundle.
Still missing
No RNA assay data are available (BP7_Strong(RNA)/BP7_Moderate(RNA) paths cannot be evaluated), though BP7 is not applicable regardless because the variant is missense rather than synonymous/deep intronic.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.014. BayesDel score = -0.568457.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
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 7.1.5.
The current version is 11.0.07.
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