Classification rationale

BP1 VUS

PALB2 c.194C>T

The PALB2 NM_024675.4:c.194C>T (NP_078951.2:p.(Pro65Leu), p.(P65L)) variant has been reported in ClinVar, but no expert panel classification is available.¹ This variant is present in gnomAD v4.1 at 0.00577% (93/1612258 alleles) with a highest observed population frequency of 0.00961%, which is below the PALB2 BS1 threshold of 0.01% and above the PM2_Supporting threshold of 0.000333%.² SpliceAI predicts no significant splice impact (max delta score 0.00), and missense predictor scores are low (REVEL 0.029; BayesDel -0.55193), although the PALB2 expert specification does not use missense computational predictors for PP3 or BP4 in this setting.³

BP1 → VUS

1 clinvar ↗

2 gnomad_v4 ↗cspec ↗

3 spliceai ↗revelbayesdelcspec ↗

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

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.76831e-05; MAF= 0.00577%, 93/1612258 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 9.6083e-05; MAF= 0.00961%, 6/62446 alleles, homozygotes = 0); grpmax FAF= 5.965e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.59565e-05; MAF= 0.00460%, 13/282876 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.28908e-05; MAF= 0.00929%, 12/129184 alleles, homozygotes = 0); grpmax FAF= 5.377e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0058% · 93 / 1,612,258
0 hom · FAF 0.006%

Remaining individuals 6 / 62,446	0.0096%
European (non-Finnish) 85 / 1,178,446	0.0072%
East Asian 1 / 44,884	0.0022%
African/African American 1 / 74,870	0.0013%

+ 6 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0046% · 13 / 282,876
0 hom · FAF 0.0054%

European (non-Finnish) 12 / 129,184	0.0093%
East Asian 1 / 19,954	0.005%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is present in ClinVar (Variation ID: 128124); submission details unavailable.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.029. BayesDel score = -0.55193.

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 previously been reported in somatic cancers (COSMIC; COSV105056546, n = 2 times).

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 · 8 PMIDs not cited in assessment

25356972 ↗ BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. CLINVAR

26564480 ↗ Mutation analysis of PALB2 gene in French breast cancer families. CLINVAR

28779002 ↗ Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. CLINVAR

31586400 ↗ A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor. CLINVAR

33139182 ↗ PALB2 Variants: Protein Domains and Cancer Susceptibility. CLINVAR

34326862 ↗ Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. CLINVAR

20301425 ↗ PMID:20301425 CLINVAR

20582465 ↗ PALB2 analysis in BRCA2-like families. CLINVAR