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 ↗

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 · 14 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

BS1 strong Benign

This variant is present in gnomAD v2.1 with a highest non-founder population filter allele frequency of 0.00037674 in East Asian samples, which is above the ENIGMA BRCA2 BS1 strong threshold of 0.0001. This supports BS1 at strong strength.

gnomAD v2.1 East Asian AF 0.000653239 (12/18370).gnomAD v2.1 grpmax FAF 0.00037674.

cspec ↗gnomad_v2 ↗

BP4 supporting Benign

This intronic variant lies outside the native donor and acceptor +/-1,2 splice sites, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the ENIGMA BRCA2 BP4 threshold of <=0.10. This supports BP4 at supporting strength.

Variant location c.7976+24.SpliceAI max delta score 0.00.

cspec ↗spliceai ↗

BP7 supporting Benign

This intronic variant is located at +24, which is beyond the conserved donor motif position +7 used in the ENIGMA BRCA2 BP7 rule, and BP4 is met because SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. This supports BP7 at supporting strength.

Variant location c.7976+24.SpliceAI max delta score 0.00.BP4 criteria are satisfied.

cspec ↗spliceai ↗

Assessed · not applied · 4 not met · 10 not assessed

Pathogenic

PVS1 This intronic variant is at c.7976+24, outside the canonical +/-1,2 splice consensus positions and outside the default null-variant categories used for PVS1.

PS1 No confirmed pathogenic or likely pathogenic comparator with the same demonstrated splicing effect was identified, so PS1 was not assessed.

PS3 No calibrated functional assay result for this specific variant was identified in the reviewed BRCA2 functional evidence sources, so PS3 was not assessed.

PS4 No case-control study or quantitative enrichment data showing a significant excess of this variant in affected individuals were identified, so PS4 was not assessed.

PM2 This variant is present in gnomAD rather than absent from controls.

PM3 No evidence was identified that this variant occurred in trans with another BRCA2 pathogenic variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed.

PP1 No segregation data were identified for this variant, so PP1 was not assessed.

PP3 Available computational evidence does not support a splice-altering effect.

PP4 No variant-specific clinical-history likelihood-ratio entry was identified in the reviewed BRCA2 ENIGMA clinical-history resource, so PP4 was not assessed.

Benign

BA1 The ENIGMA BRCA2 BA1 threshold is a non-founder population filter allele frequency greater than 0.001 in gnomAD v2.1 and/or v3.1.

BS2 No qualifying observations in individuals lacking features of BRCA2-related Fanconi anemia were identified for this variant, so BS2 was not assessed.

BS3 No calibrated functional assay showing no damaging effect for this specific variant was identified in the reviewed BRCA2 functional evidence sources, so BS3 was not assessed.

BS4 No quantitative lack-of-segregation data were identified for this variant, so BS4 was not assessed.

BP5 No variant-specific clinical-history likelihood-ratio entry supporting a benign direction was identified in the reviewed BRCA2 ENIGMA clinical-history resource, so BP5 was not assessed.

N/A · 11 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6

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

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