Classification rationale

BP1 VUS

PALB2 c.154G>A

The PALB2 c.154G>A (p.Val52Ile) variant has been reported in ClinVar with conflicting single-submitter interpretations of uncertain significance and likely benign.¹ This variant is absent from gnomAD v2.1 and is present at very low overall frequency in gnomAD v4.1 (3/1,614,050 alleles; 0.00019%), but the highest observed subpopulation frequency is 0.00160% (1/62,510 alleles), which is above the PALB2 PM2 threshold exception and remains below the BS1 and BA1 population thresholds.² SpliceAI predicts no significant splice impact (max delta score 0.01), and REVEL (0.045) and BayesDel (-0.518425) are low; however, the PALB2 VCEP does not use PP3 or BP4 for missense variants, while BP1 is applicable to all PALB2 missense variants.³

BP1 → VUS

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_024675.4 · variants mapped to exon structure

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 1 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 · 1

Strength Supporting Moderate Strong Very strong

BP1 supporting Benign

This variant is a missense substitution, and the PALB2 VCEP applies BP1 to all missense variants because pathogenic missense variation in PALB2 is considered exceedingly rare relative to truncating disease-causing variants.

p.(Val52Ile) missense consequencePALB2 VCEP BP1 applies to all missense variants

cspec ↗

Assessed · not applied · 4 not met · 5 not assessed

Pathogenic

PVS1 This variant is a missense substitution, p.(Val52Ile), and does not fall into the PALB2 loss-of-function variant categories used for PVS1.

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

PM2 This variant is absent from gnomAD v2.1 and is very rare overall in gnomAD v4.1 (3/1,614,050 alleles; 0.00019%).

PM3 No evidence was identified that this variant has been observed in trans with a pathogenic PALB2 variant in a proband with Fanconi anemia or other qualifying recessive disease context.

PP1 No segregation data were identified for this variant.

Benign

BA1 Population frequency is well below the PALB2 BA1 threshold.

BS1 Population frequency is below the PALB2 BS1 threshold.

BS2 No evidence was identified that this variant has been observed in the number of unaffected individuals required for PALB2 BS2 scoring.

BS4 No lack-of-segregation data were identified for this variant.

N/A · 18 PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · 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= 1.85868e-06; MAF= 0.00019%, 3/1614050 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59974e-05; MAF= 0.00160%, 1/62510 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,614,050
0 hom · FAF 2.8e-05%

Remaining individuals 1 / 62,510	0.0016%
European (non-Finnish) 2 / 1,179,990	0.00017%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

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 (1 clinical laboratory) and as Likely benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.045. BayesDel score = -0.518425.

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

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