Classification rationale

PM2 BP1 VUS

PALB2 c.2945G>T missense · exon 9

PM2 (Supporting): absent from gnomAD v4.1 exomes (AF 0), below the <=1/300,000 VCEP frequency threshold. BP1 (Supporting): the PALB2 VCEP applies BP1 to all missense variants given the low rate of pathogenic missense changes in PALB2. Overall: VUS (Uncertain Significance - Conflicting Evidence), per Rule 31 combining PM2 (Pathogenic.Supporting) with BP1 (Benign.Supporting).

PM2 + BP1 → VUS

Gene diagram · NM_024675.4 · variants mapped to exon structure

PALB2 NM_024675.4

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

Met (Supporting): absent from gnomAD v4.1 exomes (AF 0), satisfying the VCEP frequency threshold of <=1/300,000.

ClinGen HBOP PALB2 v1.2 CSPEC (cspec, version 1.2) rule: PM2 = Frequency <=1/300,000 (0.000333%) in gnomAD v4 dataset, strength Supporting.gnomAD v4.1 exome query for chr16-23623020-C-A (GRCh38) returned search_status 'absent' (found: false); an observed frequency of 0 is <= the 0.000333% (1/300,000) PM2 threshold.Corroborating absence from gnomAD v2.1 exomes (16-23634341-C-A, GRCh37) and gnomAD-Canada v1.0 genomes strengthens the rarity assertion for PM2.

cspec ↗gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

BP1 supporting Benign

Met (Supporting): the PALB2 VCEP applies BP1 to all missense variants, including p.(Gly982Val), given the low rate of pathogenic missense changes.

ClinGen HBOC VCEP PALB2 v1.2 (cspec) BP1 instructions: 'Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are not yet confirmed or refuted but are thought to be exceedingly rare. Given the very low likelihood that missense variants are pathogenic, this rule applies to all missense variants in PALB2.'Variant consequence (prefetch normalization): NM_024675.4:c.2945G>T is a substitution predicted to produce p.(Gly982Val) (NP_078951.2), i.e., a missense change in exon 9; VCEP BP1 Supporting rule: 'Apply to all missense variants.'

cspec ↗

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

Pathogenic

PS4 Not met: PS4 requires a case-control study (p <= 0.05, OR >= 3), and no case-control or enrichment data exist for this variant.

PM3 Not assessed: no proband, family, or phase data were available to determine whether the variant occurs in trans with a pathogenic PALB2 allele.

PP1 Not assessed: no family or segregation data were available to compute the required LOD >= 0.3 or Bayes factor >= 2:1.

PP3 Not met: splice-based PP3 requires SpliceAI >= 0.2, and the max delta is 0.003; the VCEP prohibits missense predictors.

Benign

BA1 Not met: BA1 requires gnomAD filtering AF > 0.1%, and the variant is absent (AF 0).

BS1 Not met: BS1 requires gnomAD filtering AF > 0.01%, and the variant is absent (AF 0).

BS2 Not met: no observations of this variant in individuals inconsistent with the expected phenotype exist; it is absent from gnomAD and ClinVar.

BS4 Not assessed: no non-segregation data were available to compute the required LOD <= -0.32 or LR <= 0.48.

N/A · 18 PVS1 · 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.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

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 Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.158. BayesDel score = -0.366285.

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

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots