BRCA2

Final classification

Likely Benign

BRCA2 c.8039A>G · p.Asp2680Gly

BRCA2

NM_000059.4:c.8039A>G (p.Asp2680Gly) is a missense variant in exon 18 of BRCA2, located within the DNA binding domain (aa 2481-3186).

Gene

BRCA2

Transcript

NM_000059.4

HGVS · transcript:coding

NM_000059.4:c.8039A>G

Consequence

N/A

GRCh38

chr13:32363241 A>G

GRCh37

chr13:32937378 A>G

Basis ENIGMA BRCA2 VCEP v1.2 point-based scoring system applied to conflicting pathogenic and benign evidence: BS3_Strong (-4) + PM2_Supporting (+1) = -3 points, which maps to the Likely Benign range (-6 to -2). The ENIGMA framework explicitly directs use of the point system when both pathogenic and benign criteria are met. ▾

ENIGMA BRCA2 VCEP v1.2 point-based scoring system applied to conflicting pathogenic and benign evidence: BS3_Strong (-4) + PM2_Supporting (+1) = -3 points, which maps to the Likely Benign range (-6 to -2). The ENIGMA framework explicitly directs use of the point system when both pathogenic and benign criteria are met.

Classification rationale

PM2 BS3 Likely Benign

BRCA2 c.8039A>G

NM_000059.4:c.8039A>G (p.Asp2680Gly) is a missense variant in exon 18 of BRCA2, located within the DNA binding domain (aa 2481-3186).¹ The ENIGMA BRCA2 VCEP Table 9 assigns BS3 (Strong) to this variant based on calibrated functional assay data from Richardson et al. 2021 (PMID:33609447), which demonstrates that p.Asp2680Gly exhibits homologous recombination activity similar to benign control variants.² The variant is absent from gnomAD v2.1 and ultra-rare in gnomAD v4.1 (AF 8.67e-06, grpmax FAF 5.42e-06), satisfying PM2_Supporting per ENIGMA VCEP criteria.³ In silico predictors do not meet ENIGMA VCEP thresholds for PP3 (BayesDel 0.285 < 0.30) or BP4 (BayesDel 0.285 > 0.18). SpliceAI predicts no splicing impact (delta 0.01).⁴ No case-control, segregation, or clinical-history LR data are available to support PS4, PP1, PP4, BS4, or BP5.⁵ Applying the ENIGMA point system: BS3_Strong (-4) + PM2_Supporting (+1) = -3 points, which falls in the Likely Benign range (-6 to -2).⁶

PM2 + BS3 → Likely Benign

1 gnomad_v4 ↗cspec ↗

2 vcep_specifications_table9_v1_2_2024_11_18PMID:33609447 ↗

3 gnomad_v2 ↗gnomad_v4 ↗

4 bayesdelspliceai ↗revel

5 vcep_humu_40_1557_s001vcep_pmid_31853058_brca2_clinical_history_lr

6 final_classification_framework

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

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 13 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

NM_000059.4:c.8039A>G is absent from gnomAD v2.1 (non-cancer, exome only subset), satisfying the ENIGMA BRCA2 VCEP PM2_Supporting rule for absence from an outbred population control dataset.

Absent from gnomAD v2.1gnomAD v4.1 AF 8.67e-06 (14/1614

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

✓

BS3 strong Benign

The ENIGMA BRCA2 VCEP Table 9 assigns BS3 (Strong) to NM_000059.4:c.8039A>G (p.Asp2680Gly). One calibrated study (Richardson 2021, PMID:33609447) reports that this variant exhibits protein function similar to benign control variants in a validated functional assay of BRCA2 homologous recombination activity.

VCEP Table 9: BS3_Strong assignedRichardson 2021 (PMID:33609447): Neutral functional resultSuppT4: No functional impact

PMID:33609447 ↗

Assessed · not applied

Pathogenic

PS1 No previously classified pathogenic missense variant at the same amino acid residue (Asp2680) was identified.

PS3 The ENIGMA BRCA2 VCEP Table 9 assigns BS3 (Strong) to this variant based on calibrated functional data from Richardson 2021 (PMID:33609447), reporting protein function similar to benign control variants.

PS4 No case-control data demonstrating significantly increased prevalence of NM_000059.4:c.8039A>G in affected individuals compared to controls is available.

PP1 No co-segregation data is available for NM_000059.4:c.8039A>G.

PP3 Although p.Asp2680Gly is located within the BRCA2 DNA binding domain (aa 2481-3186), the ENIGMA VCEP PP3 rule requires BayesDel no-AF score ≥0.30.

PP4 The variant is absent from the Li et al.

Benign

BA1 The ENIGMA BRCA2 VCEP BA1 rule requires filter allele frequency >0.1% (FAF >0.001).

BS1 The ENIGMA BRCA2 VCEP BS1_Supporting threshold requires FAF >0.002% (FAF >0.00002).

BS2 BS2 requires proband-level data to assess absence of Fanconi Anemia features, scored per the ENIGMA Specifications Table 8 point system.

BS4 No lack-of-segregation data are available for NM_000059.4:c.8039A>G.

BP4 The ENIGMA BRCA2 VCEP BP4 rule for missense variants inside a clinically important functional domain requires BayesDel no-AF ≤0.18 AND SpliceAI ≤0.1.

BP5 The variant is absent from the Li et al.

BP7 BP7 applies to mRNA assay data showing no damaging effect.

N/A · 10 PVS1 · PS2 · PM1 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 8.67362e-06; MAF= 0.00087%, 14/1614090 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.19969e-05; MAF= 0.00320%, 2/62506 alleles, homozygotes = 0); grpmax FAF= 5.42e-06.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00087% · 14 / 1,614,090
0 hom · FAF 0.00054%

Remaining individuals 2 / 62,506	0.0032%
European (non-Finnish) 12 / 1,179,974	0.001%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 Uncertain significance (6 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 52482)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.849. BayesDel score = 0.285282.

SpliceAI ↗

Functional Likely Neutral

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.

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 ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & References.

Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-binding-domain variants of uncertain significance.

PMID 33609447 ↗ · Richardson ME et al. · 2021 Mar 4 CLINVAR · functional

Searched

c.8039A>Gp.Asp2680GlyD2680GNM_000059.4:c.8039A>G

Found

Richardson et al. 2021 performed functional assessment of BRCA2 DNA-binding domain variants using a validated homologous recombination assay. p.Asp2680Gly (c.8039A>G) was classified as Neutral, exhibiting HR activity similar to benign control variants.

Variant

✓ Names this variant

Applied to

→BS3 supports · met

Why

Variant-specific functional data confirms neutral effect on BRCA2 homologous recombination; referenced in BS3_Strong assessment per ENIGMA VCEP Table 9.

Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID:33609447) (BS3 met).

Location Cited by ENIGMA VCEP Table 9; specific variant listed in Supplementary Table 13 (ST13) as NoImpact · Context Validated homologous recombination assay, mammalian cells

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

29394989 ↗ Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. ONCOKB

20104584 ↗ Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. CLINVAR

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

29884841 ↗ Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. CLINVAR

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