BRCA2

Final classification

Likely Benign

BRCA2 c.6698C>A · p.Ala2233Asp

BRCA2

Gene

BRCA2

Transcript

NM_000059.4

HGVS · transcript:coding

NM_000059.4:c.6698C>A

Consequence

N/A

GRCh38

chr13:32341053 C>A

GRCh37

chr13:32915190 C>A

Basis No pathogenic criteria are met. Three benign criteria are met: BP1_Strong (missense outside clinically important functional domains, SpliceAI delta=0.0), BS4_Moderate (Parsons et al. 2019 multifactorial combined LR=0.177, IARC Class 2), and BP5_Supporting (Li et al. 2020 clinical history LR=0.3604). Per ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3, the combination of 1 Strong Benign + 1 Supporting Benign satisfies the Likely Benign classification rule. BS4_Moderate provides additional corroborating evidence. ▾

No pathogenic criteria are met. Three benign criteria are met: BP1_Strong (missense outside clinically important functional domains, SpliceAI delta=0.0), BS4_Moderate (Parsons et al. 2019 multifactorial combined LR=0.177, IARC Class 2), and BP5_Supporting (Li et al. 2020 clinical history LR=0.3604). Per ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3, the combination of 1 Strong Benign + 1 Supporting Benign satisfies the Likely Benign classification rule. BS4_Moderate provides additional corroborating evidence.

Classification rationale

BS4BP1BP5 Likely Benign

BRCA2 c.6698C>A

BRCA2 c.6698C>A (p.Ala2233Asp) is a missense variant in exon 11, located at amino acid 2233, which is outside both ENIGMA-defined clinically important functional domains (PALB2 binding domain aa 10-40 and DNA binding domain aa 2481-3186). SpliceAI predicts no splicing impact (max delta = 0.0). This meets BP1_Strong per ENIGMA v1.2 specifications.¹ In a large-scale multifactorial likelihood analysis by Parsons et al. 2019 (PMID:31131967), this variant received a combined likelihood ratio of 0.177 and posterior probability of pathogenicity of 0.0036, corresponding to IARC Class 2 (Likely Benign). This meets BS4_Moderate (LR ≤0.23).² Clinical history likelihood ratio analysis by Li et al. 2020 (PMID:31853058), based on 7 probands, yielded an LR of 0.3604, meeting BP5_Supporting (LR ≤0.48). The personal and family cancer history of carriers is more consistent with a benign variant than a pathogenic BRCA2 variant.³ The variant is present at very low frequency in gnomAD (v2.1: 2/251,286 alleles; v4.1: 31/1,613,926 alleles including 1 homozygote), which is insufficient for BA1 or BS1 but also precludes PM2_Supporting. No variant-specific functional assay data are available in ENIGMA Table 9.⁴ Combining criteria per ENIGMA Table 3: BP1_Strong + BS4_Moderate satisfies the Likely Benign combination rule (1 Strong Benign + 1 Moderate Benign). BP5_Supporting provides additional corroborating benign evidence. No pathogenic criteria are met.⁵

BS4 + BP1 + BP5 → Likely Benign

1 cspec ↗spliceai ↗

2 vcep_humu_40_1557_s001PMID:31131967 ↗

3 vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗

4 gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_table9_v1_2_2024_11_18

5 final_classification_framework

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

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 11 assessed

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

BS4 moderate Benign

Parsons et al. 2019 (PMID:31131967) multifactorial likelihood analysis yields a combined LR of 0.177 (posterior probability 0.0036, IARC Class 2 — Likely Benign). This meets the BS4_Moderate threshold (LR ≤0.23). The analysis integrates co-occurrence LR (1.13) and family history LR (0.16) across multiple data sources.

Parsons et al. 2019 SuppT1: Combined LR = 0.177Posterior probability = 0.0036IARC Class 2 (Likely Benign).

PMID:31131967 ↗

✓

BP1 strong Benign

Missense variant at codon 2233 lies outside both ENIGMA-defined clinically important functional domains (PALB2 binding domain aa 10-40 and DNA binding domain aa 2481-3186). SpliceAI max delta = 0.0 (≤0.1), confirming no predicted splicing impact. Meets ENIGMA BP1_Strong criteria.

A2233D at aa 2233outside PALB2 binding domain (aa 10-40) and DNA binding domain (aa 2481-3186).SpliceAI max delta score = 0.00

cspec ↗spliceai ↗

✓

BP5 supporting Benign

Li et al. 2020 (PMID:31853058) clinical history likelihood ratio is 0.3604 (based on 7 probands), meeting the ENIGMA BP5_Supporting threshold of LR ≤0.48. This indicates the personal and family cancer history of carriers is more consistent with a benign variant than a pathogenic BRCA2 variant.

Li et al. 2020 clinical history LR = 0.3604based on 7 probands.Meets BP5_Supporting threshold (LR ≤0.48).

PMID:31853058 ↗

Assessed · not applied

Pathogenic

PS1 No previously classified pathogenic or likely pathogenic missense variant at BRCA2 codon 2233 (Ala) was identified in ENIGMA reference sets or ClinVar.

PS3 No variant-specific functional assay data found in ENIGMA Specifications Table 9 or in published literature.

PS4 The combined multifactorial likelihood ratio from Parsons et al.

PM2 ENIGMA PM2_Supporting requires absence from controls in gnomAD outbred populations.

PP1 No co-segregation data available for this variant.

PP4 Li et al.

Benign

BA1 gnomAD v4.1 grpmax filter allele frequency (FAF) is 1.53e-05 (0.00153%), far below the ENIGMA BA1 threshold of FAF >0.1% (0.001).

BS1 gnomAD v4.1 grpmax FAF = 1.53e-05 (0.00153%) is below even the BS1_Supporting threshold of FAF >0.002% (0.00002).

BS2 One homozygote is observed in gnomAD v4.1 (31 total alleles), but no phenotypic data are available to determine whether this individual lacked features of Fanconi Anemia, as required by ENIGMA BS2.

BS3 No variant-specific functional assay data found in ENIGMA Specifications Table 9.

BP7 BP7_Strong (RNA) requires well-established mRNA assay data showing no damaging effect on transcript profile.

N/A · 14 PVS1 · PS2 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP3 · PP5 · BP2 · BP3 · BP4 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.92078e-05; MAF= 0.00192%, 31/1613926 alleles, homozygotes = 1) and has highest observed frequency in the Remaining individuals population (AF= 6.40082e-05; MAF= 0.00640%, 4/62492 alleles, homozygotes = 0); grpmax FAF= 1.533e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 7.95906e-06; MAF= 0.00080%, 2/251286 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15839e-05; MAF= 0.00616%, 1/16238 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0019% · 31 / 1,613,926
1 hom · FAF 0.0015%

Remaining individuals 4 / 62,492	0.0064%
European (non-Finnish) 26 / 1,179,920	0.0022% 1 hom
African/African American 1 / 75,026	0.0013%

+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0008% · 2 / 251,286
0 hom

African/African American 1 / 16,238	0.0062%
European (non-Finnish) 1 / 113,638	0.00088%

+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

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 Likely benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 52159)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.602. BayesDel score = 0.149919.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.

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

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 8 further PMIDs triaged but not cited — see Sources & References.

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

PMID 31131967 ↗ · Parsons MT et al. · 2019 Sep CLINVAR · splicing rna

Searched

c.6698C>Ap.Ala2233AspA2233D6698

Found

Variant c.6698C>A (p.Ala2233Asp) included in large-scale BRCA2 multifactorial likelihood analysis. Combined LR = 0.177; posterior probability = 0.0036; IARC Class 2 (Likely Benign). Co-occurrence LR = 1.13, family history LR = 0.16.

Variant

✓ Names this variant — characterised directly

Applied to

→BS4 supports · met

Why

Multifactorial combined LR of 0.177 supports BS4_Moderate; variant classified as IARC Class 2 (Likely Benign) in this analysis.

Not present in main text; variant-level data extracted from SuppT1 spreadsheet.

Location Supplementary Table 1 (SuppT1), row for c.6698C>A · full text

Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model

PMID 31853058 ↗

Searched

c.6698C>Ap.Ala2233AspA2233D6698

Found

Variant c.6698C>A included in clinical history likelihood ratio analysis. LOG(LR) = -1.02, LR = 0.36 based on 7 probands. The personal and family cancer history of carriers is more consistent with a benign variant.

Variant

✓ Names this variant

Applied to

→BP5 supports · met

Why

Clinical history LR of 0.36 supports BP5_Supporting.

Not present in main text; variant-level data extracted from clinical history LR spreadsheet.

Location Supplementary MOESM3 table (converted to PMID_31853058_BRCA2_clinical_history_LR.xlsx), row for BRCA2 c.6698C>A

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

18724707 ↗ Computational and structural investigation of deleterious functional SNPs in breast cancer BRCA2 gene. CLINVAR

25682074 ↗ Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer. 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

31911673 ↗ Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". CLINVAR

10923033 ↗ The breast cancer information core: database design, structure, and scope. CLINVAR

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

18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR

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