Classification rationale

BP4BP6BP7 Likely Benign

BRCA2 c.9396A>G synonymous · exon 25

BP4 supporting benign: SpliceAI maximum delta 0.003 is below the ENIGMA threshold of 0.1. BP6 supporting benign: exact ClinVar expert-panel classification is Likely benign. BP7 supporting benign: synonymous variant with no predicted splice impact satisfies the ENIGMA BP7 rule alongside BP4.

BP4 + BP6 + BP7 → Likely Benign

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 · 15 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

BP4 supporting Benign

Met, supporting: SpliceAI maximum delta 0.003 is below the ENIGMA BP4 threshold of <=0.1 for this synonymous variant in the DNA-binding domain.

The ENIGMA BRCA2 V1.2 specification states that BP4 applies to a silent variant inside a clinically important functional domain when SpliceAI <=0.1; the BRCA2 DNA-binding domain is amino acids 2481-3186.Lys3132 is within the BRCA2 DNA-binding domain.SpliceAI returned DS_AG 0.000, DS_AL 0.000, DS_DG 0.003, and DS_DL 0.000; the maximum delta is 0.003.

cspec ↗spliceai ↗

BP6 supporting Benign

Met, Supporting: exact ClinVar expert-panel classification is Likely benign, satisfying the requested BP6 rule.

ClinVar exactly matches NM_000059.4:c.9396A>G and reports Likely benign with review status reviewed by expert panel.The expert-panel classification is distinct from the ordinary laboratory submissions and aggregate submission counts, which were not used for BP6.ENIGMA lists BP6 as not applicable; the requested exact-variant expert-panel rule was applied as the governing override.

clinvar ↗cspec ↗

BP7 supporting Benign

Met, supporting: the synonymous variant has SpliceAI maximum delta 0.003, satisfying BP4 and the ENIGMA BP7 requirement for silent variants.

The ENIGMA BRCA2 V1.2 specification states that BP7 Supporting applies to silent variants inside a clinically important functional domain if BP4 is met, and is applied in addition to BP4 for synonymous variants.The variant is synonymous and encodes p.(Lys3132=); the residue lies within the BRCA2 DNA-binding domain.BP4 is met from SpliceAI maximum delta 0.003, below the <=0.1 no-impact threshold.

cspec ↗spliceai ↗

Assessed · not applied · 3 not met · 12 not assessed

Pathogenic

PS3 Not assessed: no variant-specific protein-function or combined mRNA/protein assay was found, and SpliceAI maximum delta 0.003 is not PS3 evidence.

PS4 Not assessed: no variant-specific case-control p-value, OR >=4, or confidence interval excluding 2.0 was available.

PM2 Not assessed: required non-cancer absence is unknown, while all-comers gnomAD confirms presence at 3/251368 and 25/1614148 alleles.

PM3 Not assessed: no Fanconi Anemia phenotype, pathogenic BRCA2 variant in trans, phase, or PM3 point-bearing proband observation is available.

PP1 Not assessed: no segregation observations or quantitative LR are available, so the ENIGMA PP1 thresholds of 2.08, 4.3, 18.7, and 350 cannot be applied.

PP3 Not met: SpliceAI maximum delta 0.003 is below the ENIGMA PP3 threshold of >=0.2 for synonymous variants.

PP4 Not assessed: no exact-variant combined clinical LR was available for comparison with the PP4 supporting threshold LR >=2.08.

PP5 Not met: the exact ClinVar expert-panel classification is Likely benign, whereas PP5 requires Pathogenic or Likely pathogenic.

Benign

BA1 Not assessed: the VCEP-required non-cancer frequencies failed, so the BA1 threshold of FAF > 0.001 cannot be evaluated.

BS1 Not assessed: the VCEP-required non-cancer frequencies failed, so the BS1 FAF thresholds of >0.00002 to 0.0001 cannot be evaluated.

BS2 Not assessed: gnomAD reports 0 homozygotes, but no healthy-adult observations or ENIGMA Table 8 point assignments are available for BS2.

BS3 Not assessed: no variant-specific benign protein-function or combined mRNA/protein assay was found, and SpliceAI maximum delta 0.003 cannot establish BS3.

BS4 Not assessed: no affected-relative non-segregation data or quantitative LR are available, so the ENIGMA BS4 thresholds of 0.48, 0.23, 0.05, and 0.00285 cannot be applied.

BP1 Not met: SpliceAI max delta 0.003 is permissive, but residue 3132 lies inside the excluded DNA-binding domain aa 2481-3186.

BP5 Not assessed: no exact-variant clinical LR was available for comparison with the BP5 supporting inequality LR <=0.48.

N/A · 10 PVS1 · PS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.5488e-05; MAF= 0.00155%, 25/1614148 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000329924; MAF= 0.03299%, 2/6062 alleles, homozygotes = 0); grpmax FAF= 8.139e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.19347e-05; MAF= 0.00119%, 3/251368 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15157e-05; MAF= 0.00615%, 1/16256 alleles, homozygotes = 0).

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0015% · 25 / 1,614,148
0 hom · FAF 0.0081%

Middle Eastern 2 / 6,062	0.033%
African/African American 11 / 75,062	0.015%
Remaining individuals 5 / 62,504	0.008%
South Asian 2 / 91,080	0.0022%
European (non-Finnish) 5 / 1,179,990	0.00042%

+ 5 not observed (Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0012% · 3 / 251,368
0 hom

African/African American 1 / 16,256	0.0062%
South Asian 1 / 30,614	0.0033%
European (non-Finnish) 1 / 113,680	0.00088%

+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (11 clinical laboratories) and as Benign (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely Benign (1 clinical laboratory) and as likely benign (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 184747)

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

19305347 ↗ ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. CLINVAR

23918944 ↗ Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation c CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mende CLINVAR

27854360 ↗ Recommendations for reporting of secondary findings in clinical exome and genome CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification crite CLINVAR

34012068 ↗ ACMG SF v3.0 list for reporting of secondary findings in clinical exome and geno CLINVAR

35802134 ↗ ACMG SF v3.1 list for reporting of secondary findings in clinical exome and geno CLINVAR

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