Classification rationale

PM2 BP1 Uncertain Significance - Conflicting Evidence

PALB2 c.2734T>G

The PALB2 c.2734T>G (p.Trp912Gly) variant has not been observed in COSMIC and has been reported in ClinVar as Uncertain Significance, including expert-panel review.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing its observed population frequency below the PALB2 PM2_Supporting threshold of 0.000333%.² SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, and although REVEL and BayesDel scores are available, the PALB2 expert-panel specification does not use missense computational predictors for PP3 or BP4.³

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 · 9 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. Its observed population frequency is therefore below the PALB2 PM2_Supporting threshold of 1 in 300,000 (0.000333%), supporting PM2 at supporting strength.

Absent from gnomAD v4.1.Absent from gnomAD v2.1.

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

BP1 supporting Benign

This variant is a missense substitution, and the PALB2 expert-panel specification applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism and true pathogenic missense variants are thought to be very rare. BP1 is met at supporting strength.

Variant protein consequence is p.Trp912Gly.PALB2 VCEP instructs BP1 for all missense variants.

cspec ↗

Assessed · not applied · 9 not met · 0 not assessed

Pathogenic

PVS1 This missense variant does not fall into the PALB2 loss-of-function variant categories used for PVS1, and SpliceAI does not support a splice-disrupting effect (max delta score 0.03).

PS4 This variant has been reported in ClinVar, but no case-control study showing significant enrichment in affected individuals was identified.

PM3 No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in a proband meeting the PALB2 Fanconi anemia scoring framework.

PP1 No segregation data were identified for this variant.

PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, which is below the PALB2 PP3 splicing threshold of 0.2.

Benign

BA1 This variant is absent from gnomAD v4.1 and therefore is below the PALB2 BA1 threshold of greater than 0.1% filtering allele frequency.

BS1 This variant is absent from gnomAD v4.1 and therefore is below the PALB2 BS1 threshold of greater than 0.01% filtering allele frequency.

BS2 No evidence was identified that this variant was observed in healthy adults in a configuration that meets the PALB2 BS2 point-based framework.

BS4 No non-segregation data were identified for this variant.

N/A · 17 PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · 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 (2 clinical laboratories) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 2498117)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.562. BayesDel score = 0.00991955.

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 · 9 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

31757951 ↗ Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2. CLINVAR

34242744 ↗ Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR

18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR

20301425 ↗ BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. CLINVAR

24366376 ↗ Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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