Classification rationale

PM2 BP4BP6BP7 Likely Benign

PALB2 c.135G>A

The PALB2 c.135G>A (p.Lys45=) variant has been reported in ClinVar with an expert panel classification of likely benign.¹ This variant is present in gnomAD v4.1 at 2/1,614,022 alleles (AF 0.00012%) with a highest observed population frequency of 0.00017% and grpmax FAF 2.8e-07, which is below the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 and BA1 benign frequency thresholds.² SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.00, which supports BP4 and argues against PP3 or a splice-based loss-of-function interpretation.³

PM2 + BP4 + BP6 + BP7 → Likely Benign

1 clinvar ↗

2 gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

Gene diagram · NM_024675.3 · variants mapped to exon structure

PALB2 NM_024675.3

Fetching transcript structure from UCSC…

Applied criteria · 4 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 · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.23914e-06; MAF= 0.00012%, 2/1614022 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69495e-06; MAF= 0.00017%, 2/1179974 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.97674e-06; MAF= 0.00040%, 1/251462 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.7909e-06; MAF= 0.00088%, 1/113754 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,614,022
0 hom · FAF 2.8e-05%

European (non-Finnish)

2 / 1,179,974

0.00017%

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

gnomAD v2.1

0.0004% · 1 / 251,462
0 hom

European (non-Finnish)

1 / 113,754

0.00088%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (1 clinical laboratory) and as Likely Benign by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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