Classification rationale

BS1BP4BP7 Likely Benign

BRCA2 c.7976+24G>A

The BRCA2 NM_000059.4:c.7976+24G>A (NP_000050.3:p.?) variant has been reported in ClinVar (Variation ID 371868), although submission-level classification details were not available in the reviewed record.¹ This variant is present in population databases, including gnomAD v2.1 at 12/250842 alleles with an East Asian grpmax filter allele frequency of 0.00037674 and gnomAD v4.1 at 94/1612498 alleles; the gnomAD v2.1 frequency exceeds the ENIGMA BRCA2 BS1 strong threshold of 0.0001.² In silico splicing prediction does not support an abnormal splicing effect, with a SpliceAI maximum delta score of 0.00, consistent with BP4 and BP7 and arguing against PP3.³

BS1 + BP4 + 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 · 3 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= 5.82946e-05; MAF= 0.00583%, 94/1612498 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.0018502; MAF= 0.18502%, 83/44860 alleles, homozygotes = 0); grpmax FAF= 0.00152896.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.78389e-05; MAF= 0.00478%, 12/250842 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000653239; MAF= 0.06532%, 12/18370 alleles, homozygotes = 0); grpmax FAF= 0.00037674.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0058% · 94 / 1,612,498
0 hom · FAF 0.15%

East Asian 83 / 44,860	0.19%
South Asian 2 / 91,020	0.0022%
European (non-Finnish) 9 / 1,178,630	0.00076%

+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0048% · 12 / 250,842
0 hom · FAF 0.038%

East Asian

12 / 18,370

0.065%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is present in ClinVar (Variation ID: 371868); submission details unavailable.

ClinVar ↗

In silico

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

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

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.

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Triaged references · 8 PMIDs not cited in assessment

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

12692171 ↗ American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR

17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR

18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR

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

20065170 ↗ American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. CLINVAR