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 ↗

Gene diagram · NM_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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