Classification rationale

BS1BP4BP6BP7 Likely benign

BRCA2 c.7992T>A

The BRCA2 c.7992T>A (p.Ile2664=) variant has been reported in ClinVar, including a likely benign expert panel classification from ENIGMA and multiple likely benign clinical laboratory submissions.¹ In population databases, the variant is present at low frequency; in gnomAD v2.1 the grpmax filter allele frequency is 3.433e-05, which exceeds the BRCA2 ENIGMA BS1 Supporting threshold of 2.0e-05, and gnomAD v4.1 shows a consistent low-frequency signal with grpmax filter allele frequency 3.666e-05.² SpliceAI predicts no significant splice effect with a maximum delta score of 0.02, which is below the BRCA2 ENIGMA BP4/BP7 threshold of 0.1 and below the PP3 threshold of 0.2, supporting BP4 and BP7 rather than a deleterious splicing prediction.³

BS1 + BP4 + BP6 + BP7 → Likely benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

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 · 4 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 · 4

Strength Supporting Moderate Strong Very strong

BS1 supporting Benign

This variant meets BRCA2 ENIGMA BS1 at supporting strength because the gnomAD v2.1 grpmax filter allele frequency is 3.433e-05, which is above the BS1 Supporting threshold of 2.0e-05 and at or below the upper BS1 boundary of 1.0e-04. The highest observed population is European (non-Finnish).

gnomAD v2.1 grpmax FAF 3.433e-05population context in European non-Finnish samples

gnomad_v2 ↗cspec ↗

BP4 supporting Benign

This synonymous variant lies within the BRCA2 DNA-binding domain and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02, which is below the BRCA2 ENIGMA BP4 threshold of 0.1. REVEL and BayesDel scores were not available, but they are not required for this silent-variant BP4 rule.

SpliceAI max delta 0.02BRCA2 DNA-binding domain rule for silent variants

spliceai ↗cspec ↗

BP6 supporting Benign

Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Likely benign.

BRCA2 ENIGMA criteria applicabilityClinVar expert panel classification

cspec ↗clinvar ↗

BP7 supporting Benign

This synonymous variant is located within the BRCA2 DNA-binding domain and also meets BP4 because SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02. Under the BRCA2 ENIGMA rule, a silent variant inside a clinically important functional domain can receive BP7 at supporting strength when BP4 is met.

SpliceAI max delta 0.02BP4 prerequisite satisfied for silent variant in domain

spliceai ↗cspec ↗

Assessed · not applied · 5 not met · 10 not assessed

Pathogenic

PVS1 This synonymous variant does not create a premature termination codon, frameshift, or canonical ±1,2 splice-site change, and no RNA assay evidence was identified to support a PVS1(RNA) application.

PS1 No verified pathogenic or likely pathogenic comparator with the same predicted protein or splicing consequence was identified from the available evidence.

PS3 No variant-specific calibrated functional assay result supporting a damaging effect was identified for c.7992T>A.

PS4 No case-control enrichment data meeting the BRCA2 ENIGMA PS4 thresholds were identified for this variant.

PM2 This variant is present in population databases and therefore is not absent from controls.

PM3 No evidence was identified for occurrence with another BRCA2 variant in a proband with BRCA2-related Fanconi anemia.

PP1 No quantitative co-segregation data were identified for this variant.

PP3 Computational evidence does not support a deleterious effect.

PP4 No variant-specific clinical-history likelihood ratio meeting BRCA2 ENIGMA PP4 thresholds was identified in the available data.

Benign

BA1 The observed population frequency is below the BRCA2 ENIGMA BA1 threshold.

BS2 No point-based evidence was identified to support BS2 under the BRCA2 ENIGMA Fanconi-anemia-related framework.

BS3 No variant-specific calibrated functional assay result showing no damaging effect was identified for c.7992T>A.

BS4 No quantitative lack-of-segregation likelihood ratio meeting BRCA2 ENIGMA BS4 thresholds was identified for this variant.

BP1 This synonymous variant is located at codon 2664 within the BRCA2 DNA-binding domain (aa 2481-3186), so it does not meet the BRCA2 ENIGMA BP1 rule for silent or missense variants outside clinically important functional domains.

BP5 No variant-specific clinical-history likelihood ratio meeting BRCA2 ENIGMA BP5 thresholds was identified in the available data.

N/A · 9 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · 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= 3.65626e-05; MAF= 0.00366%, 59/1613670 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.66135e-05; MAF= 0.00466%, 55/1179916 alleles, homozygotes = 0); grpmax FAF= 3.666e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.19412e-05; MAF= 0.00319%, 8/250460 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.06801e-05; MAF= 0.00707%, 8/113186 alleles, homozygotes = 0); grpmax FAF= 3.433e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0037% · 59 / 1,613,670
0 hom · FAF 0.0037%

European (non-Finnish) 55 / 1,179,916	0.0047%
Remaining individuals 2 / 62,496	0.0032%
Admixed American 1 / 60,006	0.0017%
European (Finnish) 1 / 63,762	0.0016%

+ 6 not observed (Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0032% · 8 / 250,460
0 hom · FAF 0.0034%

European (non-Finnish)

8 / 113,186

0.0071%

+ 7 not observed (African/African American, Admixed 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 (10 clinical laboratories) and as Uncertain significance (4 clinical laboratories) and as Benign (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 52463)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

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

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 10 PMIDs not cited in assessment

21673748 ↗ Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes. CLINVAR

22505045 ↗ Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. CLINVAR

22962691 ↗ Multiple sequence variants of BRCA2 exon 7 alter splicing regulation. CLINVAR

23893897 ↗ Evaluation of a 5-tier scheme proposed for classification of sequence variants using bioinformatic and splicing assay data: inter-reviewer variability and promotion of minimum reporting guidelines. 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 Mendelian Disorders. CLINVAR

26913838 ↗ Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants. CLINVAR

28339459 ↗ Functional classification of DNA variants by hybrid minigenes: Identification of 30 spliceogenic variants of BRCA2 exons 17 and 18. CLINVAR

26332594 ↗ Identification of Medically Actionable Secondary Findings in the 1000 Genomes. CLINVAR

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

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