Classification rationale

BP1 VUS

PALB2 c.2631G>C

The PALB2 c.2631G>C (p.Trp877Cys, p.W877C) variant has not been observed in COSMIC and has been reported in ClinVar as likely benign by a single clinical laboratory. In population data, this variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at 1/1,614,170 alleles (0.00006%), with a highest observed South Asian frequency of 1/91,090 alleles (0.00110%), which is below the PALB2 BS1 and BA1 thresholds but above the PALB2 PM2 under-represented subpopulation exception threshold for a singleton observation.¹ In silico splice prediction does not support a clinically significant splice effect, with a SpliceAI maximum delta score of 0.17, which is below the PALB2 PP3 threshold of 0.2.²

BP1 → VUS

1 gnomad_v4 ↗

2 spliceai ↗

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 review Benign

This missense variant changes PALB2 p.Trp877 to cysteine. The PALB2 VCEP applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism and pathogenic missense variants are thought to be exceedingly rare.

NP_078951.2:p.(Trp877Cys)PALB2 BP1 applies to all missense variants.

cspec ↗

Assessed · not applied · 6 not met · 4 not assessed

Pathogenic

PM3 No Fanconi anemia proband data or phase-confirmed trans observations with a pathogenic PALB2 variant were identified, so PM3 cannot be assigned.

PM2 This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,614,170 alleles (0.00006%), which is below the PALB2 PM2_Supporting threshold of ≤ 0.000333%.

PS4 No PALB2 case-control data were identified showing a significant enrichment of this variant in affected individuals, and ClinVar contains only a single likely benign submitter.

PP1 No segregation data with affected relatives, LOD score, or Bayes factor were identified for this variant, so PP1 cannot be assessed.

PVS1 Germline loss of function is an established disease mechanism for PALB2, but this variant is a missense substitution p.(Trp877Cys) and does not fall into the PALB2 or generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice variants.

PP3 SpliceAI shows a maximum delta score of 0.17 for this missense variant, which is below the PALB2 PP3 splicing threshold of ≥ 0.2.

Benign

BS4 No quantitative segregation data or Bayes factor data were identified for this variant, so the PALB2 BS4 thresholds cannot be evaluated.

BS2 No data were identified showing this variant in informative unaffected individuals under the PALB2 Fanconi anemia BS2 scoring framework, so BS2 cannot be evaluated.

BS1 This variant is present in gnomAD v4.1 at 1/1,614,170 alleles (0.00006%), with a highest observed population frequency of 1/91,090 alleles in South Asian individuals (0.00110%).

BA1 This variant is present in gnomAD v4.1 at 0.00006% overall and 0.00110% in the highest observed population, both of which are below the PALB2 BA1 threshold of >0.1%.

N/A · 17 PM4 · BP6 · BP5 · BS3 · PP4 · PM6 · PM1 · BP7 · BP4 · BP2 · PP2 · PS3 · BP3 · PP5 · PM5 · PS2 · PS1

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19513e-07; MAF= 0.00006%, 1/1614170 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09782e-05; MAF= 0.00110%, 1/91090 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,614,170
0 hom

South Asian

1 / 91,090

0.0011%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))

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 Likely benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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

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