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 ↗

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 · 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 · 3

Strength Supporting Moderate Strong Very strong

BS1 strong review Benign

Population frequency supports a benign interpretation. In gnomAD v4, the grpmax filtering allele frequency is 0.088684%, which is above the PALB2 BS1 threshold of >0.01%.

gnomAD v4 grpmax FAF 0.00088684PALB2 BS1 threshold >0.01% in gnomAD v4

gnomad_v4 ↗cspec ↗

BP1 supporting review Benign

This is a missense variant, NM_024675.3:c.3249G>C (p.Glu1083Asp, p.E1083D). Under the PALB2 VCEP specification, BP1 applies to all missense variants because pathogenic missense variation is thought to be exceedingly rare in PALB2.

Variant consequence p.Glu1083Asp / p.E1083DPALB2 BP1 applies to all missense variants

cspec ↗

BP6 supporting review Benign

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

PALB2 VCEP marks BP6 not applicableClinVar expert panel classification

cspec ↗clinvar ↗

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

Pathogenic

PVS1 PVS1 was not applied.

PS4 No qualifying case-control evidence was identified for this variant.

PM2 Population frequency does not meet the PALB2 PM2_Supporting threshold.

PM3 No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in Fanconi anemia, so PM3 was not assessed.

PP1 No segregation data were identified for this variant, and no LOD score or Bayes factor was available, so PP1 was not assessed.

Benign

BA1 Population frequency does not meet the PALB2 BA1 threshold.

BS2 No data were identified showing this variant in informative unaffected individuals under the PALB2 BS2 point-based framework, so BS2 was not assessed.

BS4 No family study showing lack of segregation was identified, and no LOD score or Bayes factor was available for this variant, so BS4 was not assessed.

N/A · 17 PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · 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= 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

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