Classification rationale

BS1BP1BP6 Likely Benign

PALB2 c.3249G>C

The PALB2 c.3249G>C (p.Glu1083Asp, p.E1083D) variant has been reported in ClinVar and is classified there as benign by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.¹ In gnomAD v4, the variant has a total allele frequency of 0.00533% and a grpmax filtering allele frequency of 0.088684%, which is above the PALB2 BS1 threshold of 0.01% but below the BA1 threshold of 0.1%.² Computational data predict no significant splice effect, with a SpliceAI max delta score of 0.00; REVEL is 0.081 and BayesDel is -0.49371, although PALB2 VCEP guidance does not apply missense PP3 or BP4 for this gene.³

BS1 + BP1 + BP6 → Likely 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= 5.3285e-05; MAF= 0.00533%, 86/1613962 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.00110011; MAF= 0.11001%, 66/59994 alleles, homozygotes = 0); grpmax FAF= 0.00088684.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00021919; MAF= 0.02192%, 62/282860 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.00163657; MAF= 0.16366%, 58/35440 alleles, homozygotes = 0); grpmax FAF= 0.0013313.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0053% · 86 / 1,613,962
0 hom · FAF 0.089%

Admixed American 66 / 59,994	0.11%
European (non-Finnish) 20 / 1,179,992	0.0017%

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

gnomAD v2.1

0.022% · 62 / 282,860
0 hom · FAF 0.13%

Admixed American 58 / 35,440	0.16%
European (non-Finnish) 4 / 129,180	0.0031%

+ 6 not observed (African/African 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 (7 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Benign (2 clinical laboratories) and as likely benign (1 clinical laboratory) 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 = 0.00). REVEL score = 0.081. BayesDel score = -0.49371.

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; COSV55168291, n = 1 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