Classification rationale

BP6BP1BS1BA1 Benign

PALB2 c.2027T>C

The PALB2 c.2027T>C (p.Ile676Thr) variant has been reported in ClinVar as Benign, including a reviewed expert panel classification.¹ This variant is present in gnomAD v4.1 with an overall allele frequency of 0.01425% (230/1614160) and a highest observed population frequency of 0.37653% (226/60022 alleles in the Admixed American population), which is above the PALB2 BA1 threshold of 0.1% and the BS1 threshold of 0.01%.² In silico data do not support a splice effect, with a SpliceAI maximum delta score of 0.02; REVEL is 0.003 and BayesDel is -0.705338, but the PALB2 VCEP does not use PP3 or BP4 for missense variants.³

BP6 + BP1 + BS1 + BA1 → 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 · 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= 0.000142489; MAF= 0.01425%, 230/1614160 alleles, homozygotes = 2) and has highest observed frequency in the Admixed American population (AF= 0.00376529; MAF= 0.37653%, 226/60022 alleles, homozygotes = 2); grpmax FAF= 0.00336271.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000728337; MAF= 0.07283%, 206/282836 alleles, homozygotes = 1) and has highest observed frequency in the Admixed American population (AF= 0.00578606; MAF= 0.57861%, 205/35430 alleles, homozygotes = 1); grpmax FAF= 0.00515383.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.014% · 230 / 1,614,160
2 hom · FAF 0.34%

Admixed American 226 / 60,022	0.38% 2 hom
Remaining individuals 3 / 62,504	0.0048%
East Asian 1 / 44,888	0.0022%

+ 7 not observed (European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.073% · 206 / 282,836
1 hom · FAF 0.52%

Admixed American 205 / 35,430	0.58% 1 hom
Remaining individuals 1 / 7,222	0.014%

+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (10 clinical laboratories) and as Likely benign (4 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 = 0.02). REVEL score = 0.003. BayesDel score = -0.705338.

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