Classification rationale

PM2 BP1 Uncertain Significance - Conflicting Evidence

PALB2 c.338C>T

The PALB2 c.338C>T (p.Pro113Leu) variant has been reported in ClinVar, where the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel classified it as uncertain significance, with additional submissions of uncertain significance and likely benign.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing its observed frequency below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%).² SpliceAI predicts no splice impact with a max delta score of 0.00, and missense predictors are low (REVEL 0.012; BayesDel -0.722131); however, the PALB2 expert specification does not use PP3 or BP4 for missense prediction and applies BP1_Supporting to all missense variants.³

PM2 + BP1 → Uncertain Significance - Conflicting Evidence

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗revelbayesdelcspec ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_024675.3 · variants mapped to exon structure

PALB2 NM_024675.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 8 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed frequency is therefore below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%), so PM2_Supporting is met.

Absent from gnomAD v4.1Absent from gnomAD v2.1PALB2 VCEP PM2 threshold ≤0.000333%

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

BP1 supporting Benign

This variant is a missense substitution, and the PALB2 expert specification applies BP1 to all missense variants because pathogenic missense variants in PALB2 are thought to be exceedingly rare. BP1_Supporting is met.

Variant is missense p.Pro113LeuPALB2 VCEP BP1 applies to all missense variants

cspec ↗

Assessed · not applied · 3 not met · 5 not assessed

Pathogenic

PVS1 This missense variant does not meet PALB2 PVS1 criteria.

PS4 This variant has been reported in ClinVar, including an expert panel uncertain significance classification, but no case-control study or exact-variant enrichment data were identified to show a statistically significant increase in affected individuals.

PM3 No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in a Fanconi anemia context, and no PM3 point-based proband data were available.

PP1 No segregation data were identified for this variant, and no LOD score, Bayes factor, or affected-relative count was available to meet PALB2 PP1 thresholds.

Benign

BA1 This variant is absent from gnomAD v4.1, so its observed population frequency is below the PALB2 BA1 threshold of greater than 0.1%.

BS1 This variant is absent from gnomAD v4.1, so its observed population frequency is below the PALB2 BS1 threshold of greater than 0.01%.

BS2 No evidence was identified that this variant was observed in healthy individuals under the PALB2 BS2 point-based framework, and population database absence cannot be used for BS2.

BS4 No non-segregation data, negative LOD score, or Bayes factor was identified for this variant.

N/A · 18 PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 492220)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.012. BayesDel score = -0.722131.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 PMIDs not cited in assessment

25741868 ↗ 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. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

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