Classification rationale

BA1BP1BP6 Benign

PALB2 c.3054G>C

The PALB2 c.3054G>C (p.Glu1018Asp; E1018D) variant has been reported in ClinVar, where the aggregate classification is Benign with expert panel review.¹ This variant is present in gnomAD v4.1 at 214/1,614,106 alleles (AF 0.01326%), with highest observed East Asian frequency 187/44,876 alleles (AF 0.41670%), which is above the PALB2 BA1 threshold of 0.1%.² SpliceAI predicts no significant splice effect (max delta score 0.01), below the PALB2 PP3 splice threshold of 0.2; REVEL is 0.118 and BayesDel is -0.42024, and the PALB2 specification does not support missense PP3/BP4 use beyond its stated splice rules.³

BA1 + BP1 + BP6 → Benign

1 clinvar ↗

2 gnomad_v4 ↗cspec ↗

3 spliceai ↗revelbayesdelcspec ↗

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

PALB2 NM_024675.3

Fetching transcript structure from UCSC…

Applied criteria · 3 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= 0.000132581; MAF= 0.01326%, 214/1614106 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00416704; MAF= 0.41670%, 187/44876 alleles, homozygotes = 0); grpmax FAF= 0.00367847.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000385363; MAF= 0.03854%, 109/282850 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00526263; MAF= 0.52626%, 105/19952 alleles, homozygotes = 0); grpmax FAF= 0.00444365.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.013% · 214 / 1,614,106
0 hom · FAF 0.37%

East Asian 187 / 44,876	0.42%
Remaining individuals 19 / 62,510	0.03%
South Asian 4 / 91,076	0.0044%
Admixed American 1 / 60,008	0.0017%
European (non-Finnish) 3 / 1,180,004	0.00025%

+ 5 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.039% · 109 / 282,850
0 hom · FAF 0.44%

East Asian 105 / 19,952	0.53%
Remaining individuals 3 / 7,224	0.042%
European (non-Finnish) 1 / 129,170	0.00077%

+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (6 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as 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 = 0.01). REVEL score = 0.118. BayesDel score = -0.42024.

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; COSV55165548, 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