Classification rationale

BA1BS1BP1 Benign

BRCA2 c.4071A>C

BRCA2 ENIGMA BA1 is met because the variant exceeds the stand-alone benign frequency threshold in gnomAD: v2.1 grpmax FAF 0.00161392 and v4.1 grpmax FAF 0.00154091, both >0.001.¹ The variant is synonymous, p.(Leu1357=), and lies outside the BRCA2 clinically important domains defined by ENIGMA; with SpliceAI max delta score 0.00, this satisfies BP1_Strong.² ClinVar shows a concordant benign expert-panel assertion from ENIGMA, which supports but does not replace the VCEP rule-based classification.³

BA1 + BS1 + BP1 → Benign

1 gnomad_v2 ↗

2 cspec ↗

3 clinvar ↗

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_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 12 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

BA1 is met because the variant exceeds the BRCA2 ENIGMA BA1 filter allele frequency threshold (>0.001) in non-founder population data. In gnomAD v2.1 the grpmax FAF is 0.00161392, and in gnomAD v4.1 the grpmax FAF is 0.00154091, both above the stand-alone benign threshold.

gnomAD v2.1 grpmax FAF 0.00161392 in African/African American population.gnomAD v4.1 grpmax FAF 0.00154091; total AF 8.51244e-05, 137/1609410 alleles.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS1 Strong Benign

BS1 is also met because the variant's gnomAD filter allele frequency is well above the BRCA2 ENIGMA BS1 strong threshold (>0.0001). This is redundant once BA1 is met but remains concordant benign evidence.

gnomAD v2.1 grpmax FAF 0.00161392.gnomAD v4.1 grpmax FAF 0.00154091.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP1 Strong Benign

BP1_Strong is met under BRCA2 ENIGMA because this is a silent substitution, p.(Leu1357=), outside the BRCA2 clinically important domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186), and SpliceAI predicts no splice impact (max delta score 0.00, <=0.1).

Protein consequence p.(Leu1357=) / p.(L1357=).SpliceAI max delta score 0.00.

cspec ↗spliceai ↗

Assessed · not applied · 2 not met · 10 not assessed

Pathogenic

PS3 No calibrated functional assay evidence for this specific variant was identified in the reviewed workspace or VCEP functional table.

PS4 No qualifying case-control enrichment or ENIGMA quantitative pathogenic likelihood evidence for this specific variant was identified in the reviewed workspace/VCEP files.

PM2 The variant is not absent from controls; it is observed repeatedly in gnomAD v2.1 and v4.1.

PM3 No Fanconi-anemia-related biallelic case evidence or phase data were identified.

PP1 No quantitative segregation data were identified for this case.

PP3 SpliceAI max delta score is 0.00, far below the BRCA2 ENIGMA PP3 splicing threshold of >=0.2; the variant is synonymous, not a missense/in-frame protein-altering change.

PP4 No multifactorial clinical LR supporting pathogenicity was identified for this specific variant.

Benign

BS2 No point-based adult observation data without Fanconi anemia features were assembled for this case.

BS3 No calibrated benign functional assay result for this specific variant was identified.

BS4 No quantitative non-segregation likelihood ratio was identified for this variant.

BP5 No quantitative multifactorial likelihood ratio against pathogenicity was assembled for this variant.

BP7 No qualifying RNA assay evidence was identified.

N/A · 13 PVS1 · PS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

Allele frequency by ancestry

three datasets · side by side

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (8 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

Sources & reference links

6Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

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