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 ↗

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_024675.4 · variants mapped to exon structure

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 10 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 · 1

Strength Supporting Moderate Strong Very strong

BP1 supporting Benign

This variant is a missense change, and the PALB2 expert specification applies BP1 to all missense variants because pathogenic missense variation is thought to be very uncommon in this gene.

The variant is p.(Pro65Leu)a missense substitution.PALB2 BP1 is specified to apply to all missense variants.

cspec ↗

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

Pathogenic

PVS1 PALB2 loss of function is an established disease mechanism, but this variant is a missense substitution and does not fall into the generic null-variant categories for PVS1.

PS4 The variant has been reported in clinical databases and publications, but the available evidence does not provide a qualifying variant-specific case-control estimate with p-value ≤0.05 and odds ratio, hazard ratio, or relative risk ≥3, or lower 95% confidence interval ≥1.5, so PS4 cannot be assigned.

PM2 This variant is present in gnomAD v4.1 at 0.00577%, which is above the PALB2 PM2_Supporting threshold of 0.000333%, so PM2 is not met.

PM3 No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in individuals with Fanconi anemia, so PM3 points cannot be assigned.

PP1 No quantitative co-segregation data were identified for this variant, so the PALB2 PP1 thresholds cannot be evaluated.

PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), which is below the PALB2 PP3 threshold of 0.2 for splice-based use.

Benign

BA1 The highest observed gnomAD v4.1 population frequency is 0.00961%, which is below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met.

BS1 The highest observed gnomAD v4.1 population frequency is 0.00961%, which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met.

BS2 No qualifying observations were identified in healthy adults or other point-based PALB2 BS2 evidence, so BS2 cannot be assigned.

BS4 No quantitative segregation or lack-of-segregation data were identified for this variant, so the PALB2 BS4 thresholds based on LOD score or likelihood ratio cannot be evaluated.

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

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

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