Variant classification summary

NM_000059.4:c.6698C>A

BRCA2 · NP_000050.3:p.(Ala2233Asp) · NM_000059.4

GRCh37: chr13:32915190 C>A · GRCh38: chr13:32341053 C>A

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

BP1 strong BS4 moderate BP5 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Ala2233Asp)

gnomAD AF

1.920781993722141e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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).

3

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.

4

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.

5

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.

Final determination: Per ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3, the combination of 1 Strong Benign criterion (BP1) and 1 Supporting Benign criterion (BP5) classifies this variant as Likely Benign.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Missense variant (c.6698C>A, p.Ala2233Asp); PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon deletions).	pvs1_variant_assessment
PS1	Not met	No previously classified pathogenic or likely pathogenic missense variant at BRCA2 codon 2233 (Ala) was identified in ENIGMA reference sets or ClinVar. PS1 requires a different amino acid change at the same residue to have been established as pathogenic.	pm5_candidates vcep_supplementarytables_v1_2_2024_11_18
PS2	N/A	Not applicable for this VCEP per ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2.	cspec
PS3	Not assessed	No variant-specific functional assay data found in ENIGMA Specifications Table 9 or in published literature. The variant falls outside the clinically important functional domains (DNA binding domain aa 2481-3186, PALB2 binding domain aa 10-40), where calibrated functional assays are primarily concentrated.	vcep_specifications_table9_v1_2_2024_11_18 oncokb
PS4	Not met	The combined multifactorial likelihood ratio from Parsons et al. 2019 is 0.177, which is in the benign direction and does not support pathogenicity. No case-control study demonstrates significantly increased prevalence of this variant in affected individuals (OR ≥4 required).	vcep_humu_40_1557_s001 PMID:31131967
PS5	N/A	Not applicable for this VCEP per ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2.	cspec
PM1	N/A	Not applicable per ENIGMA BRCA1/BRCA2 Specification v1.2. PM1 is considered a component of bioinformatic analysis (PP3/BP4) and is not applied independently.	cspec
PM2	Not met	ENIGMA PM2_Supporting requires absence from controls in gnomAD outbred populations. This variant is present in gnomAD v2.1 (2/251,286 alleles; AF=7.96e-06) and v4.1 (31/1,613,926 alleles; AF=1.92e-05), including one homozygote in v4.1.	gnomad_v2 gnomad_v4
PM5	N/A	ENIGMA repurposes PM5 for protein termination codon (PTC) variants only (PM5_PTC). This is a missense variant, not a PTC.	pm5_candidates cspec
PM6	N/A	Not applicable per ENIGMA BRCA1/BRCA2 Specification v1.2.	cspec
PP1	Not assessed	No co-segregation data available for this variant. Co-segregation analysis requires quantitative LR from family studies.
PP2	N/A	Not applicable per ENIGMA BRCA1/BRCA2 Specification v1.2.	cspec
PP3	N/A	ENIGMA PP3 requires either (a) missense inside a clinically important functional domain with BayesDel no-AF ≥0.30, or (b) SpliceAI ≥0.2 for any missense variant. A2233D at aa 2233 is outside both the PALB2 binding domain (aa 10-40) and DNA binding domain (aa 2481-3186). BayesDel no-AF = 0.15 (<0.30). SpliceAI max delta = 0.0 (<0.2). Neither condition is met.	cspec spliceai revel bayesdel
PP4	Not met	Li et al. 2020 (PMID:31853058) clinical history likelihood ratio is 0.3604, which falls below the PP4_Supporting threshold of LR ≥2.08. This LR is in the benign direction and instead supports BP5.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	Not applicable for this VCEP per ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	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).	gnomad_v4
BS1	Not met	gnomAD v4.1 grpmax FAF = 1.53e-05 (0.00153%) is below even the BS1_Supporting threshold of FAF >0.002% (0.00002). The variant is too rare in population databases to apply BS1.	gnomad_v4
BS2	Not assessed	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.	gnomad_v4
BS3	Not assessed	No variant-specific functional assay data found in ENIGMA Specifications Table 9. The variant is outside the clinically important functional domains where calibrated functional assays are concentrated.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Met	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.	vcep_humu_40_1557_s001 PMID:31131967 vcep_supplementarytables_v1_2_2024_11_18
BP1	Met	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.	cspec spliceai
BP2	N/A	Not applicable per ENIGMA BRCA1/BRCA2 Specification v1.2.	cspec
BP4	N/A	ENIGMA BP4 requires the variant to be inside a clinically important functional domain (PALB2 binding aa 10-40 or DNA binding aa 2481-3186). A2233D at aa 2233 is outside both domains. Additionally, BayesDel no-AF = 0.15 does not independently trigger BP4.	cspec bayesdel spliceai
BP5	Met	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.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	Not applicable per ENIGMA BRCA1/BRCA2 Specification v1.2.	cspec
BP7	Not assessed	BP7_Strong (RNA) requires well-established mRNA assay data showing no damaging effect on transcript profile. No allele-specific mRNA splicing assay has been performed for this variant. The variant is a missense outside functional domains, making it eligible for BP7_Strong (RNA) if mRNA data were available.	cspec
BP3	N/A	In-frame deletions/insertions in repetitive regions only; this is a missense substitution.
PM3	N/A	Requires co-occurrence with a second pathogenic variant in trans in a Fanconi Anemia proband; no such data available for this missense variant.
PM4	N/A	Protein length changes (in-frame deletions/insertions, stop-loss) only; this is a missense substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.