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 ↗

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_024675.3 · variants mapped to exon structure

PALB2 NM_024675.3

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 10 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 · 3

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

This variant is present in gnomAD v4.1 with highest observed East Asian frequency 187/44,876 alleles (AF 0.41670%) and grpmax FAF 0.36785%, both above the PALB2 BA1 threshold of >0.1%. This population frequency supports BA1.

gnomAD v4.1 East Asian AF is 0.00416704.gnomAD v4.1 grpmax FAF is 0.00367847.

cspec ↗gnomad_v4 ↗

BP1 supporting Benign

This variant is a missense substitution, and the PALB2 specification states that BP1 applies to all missense variants. This supports BP1.

The variant is p.(Glu1018Asp)a missense change.PALB2 BP1 applies to all missense variants.

cspec ↗

BP6 supporting Benign

Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign.

BP6 is marked not applicable for this VCEP.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 6 not assessed

Pathogenic

PVS1 This variant is a missense substitution, not a nonsense, frameshift, or canonical ±1,2 splice variant, and no RNA evidence was identified to show a loss-of-function splicing effect.

PS1 No evidence was identified showing that this nucleotide change has the same established pathogenic amino acid or splicing consequence as a previously classified pathogenic PALB2 variant under the PALB2 PS1 splicing framework.

PS4 No case-control study or exact-variant enrichment data were identified to show this variant is significantly more common in affected individuals than in controls.

PM2 This variant is present in gnomAD v4.1 at 214/1,614,106 alleles (AF 0.01326%), which is above the PALB2 PM2_Supporting threshold of ≤0.000333%.

PM3 No evidence was identified showing this variant in trans with a pathogenic PALB2 variant in Fanconi anemia cases, so PM3 could not be applied.

PP1 No segregation data were identified for this variant, so the available evidence does not support PP1 at any strength.

PP3 SpliceAI predicts no significant splice effect for this variant (max delta score 0.01), which is below the PALB2 PP3 splice threshold of ≥0.2.

Benign

BS1 The observed gnomAD v4.1 population frequency exceeds the stricter BA1 threshold, so BS1 was not separately counted.

BS2 No point-based evidence from unaffected individuals or qualifying Fanconi anemia context was identified, so BS2 could not be applied.

BS4 No non-segregation data or quantitative evidence showing lack of segregation in affected relatives were identified, so BS4 could not be applied.

N/A · 15 PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP7

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

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