Classification rationale

BP1 VUS

PALB2 c.2329G>A

The PALB2 c.2329G>A (p.Asp777Asn; p.D777N) variant has been observed in somatic cancers in COSMIC 3 times (COSV55162903) and has not been reported in ClinVar.¹ This variant is present in gnomAD v4.1 at 35/1,614,078 alleles (AF 0.00217%), with highest observed frequency in East Asian individuals at 4/44,886 alleles (AF 0.00891%) and grpmax FAF 0.00298%, which is above the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 threshold of 0.01%.² SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), and REVEL is low at 0.038; however, PALB2 missense specifications do not use PP3 or BP4 for missense variants.³

BP1 → VUS

1 cosmicclinvar ↗

2 gnomad_v4 ↗

3 spliceai ↗revelcspec ↗

Gene diagram · NM_024675.4 · variants mapped to exon structure

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 1 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

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 2.16842e-05; MAF= 0.00217%, 35/1614078 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 8.91146e-05; MAF= 0.00891%, 4/44886 alleles, homozygotes = 0); grpmax FAF= 2.977e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.59089e-05; MAF= 0.00159%, 4/251432 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108731; MAF= 0.01087%, 2/18394 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0022% · 35 / 1,614,078
0 hom · FAF 0.003%

East Asian 4 / 44,886	0.0089%
Remaining individuals 2 / 62,506	0.0032%
European (non-Finnish) 28 / 1,180,018	0.0024%
South Asian 1 / 91,068	0.0011%

+ 6 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0016% · 4 / 251,432
0 hom · FAF 0.0019%

East Asian 2 / 18,394	0.011%
European (non-Finnish) 2 / 113,736	0.0018%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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; COSV55162903, n = 3 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

Hotspots ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

Cancer hotspots