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 ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 8 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BP1 Supporting review Benign

This is a missense variant, and the PALB2 specification applies BP1_Supporting to all missense variants.

NM_024675.4:c.2329G>ANP_078951.2:p.(Asp777Asn)PALB2 BP1 rule: apply to all missense variants

cspec ↗

Assessed · not applied · 3 not met · 5 not assessed

Pathogenic

PS4 This variant has been observed in COSMIC 3 times, but no germline case-control study showing significant enrichment in affected individuals was identified, so available evidence does not support PS4 assessment.

PM2 This variant is present in gnomAD v4.1 at 35/1,614,078 alleles (AF 0.00217%), with grpmax FAF 0.00298%.

PM3 No data were identified showing this variant in trans with a pathogenic PALB2 variant in Fanconi anemia probands, so PM3 cannot be assessed.

PP1 No segregation data were identified for this variant, so PP1 cannot be assessed.

Benign

BA1 This variant is present in gnomAD v4.1 with grpmax FAF 0.00298%, which is below the PALB2 BA1 threshold of 0.1%, so BA1 is not met.

BS1 This variant is present in gnomAD v4.1 with grpmax FAF 0.00298%, which is below the PALB2 BS1 threshold of 0.01%, so BS1 is not met.

BS2 No data were identified showing this variant in the number of unaffected individuals required by the PALB2 Fanconi anemia BS2 point system, so BS2 cannot be assessed.

BS4 No nonsegregation data were identified for this variant, so BS4 cannot be assessed.

N/A · 19 PVS1 · PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7

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

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