LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-06-03
Case ID: NM_000059.4_c.8183T_C_20260603_134815
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.8183T>C

BRCA2  · NP_000050.3:p.(Val2728Ala)  · NM_000059.4
GRCh37: chr13:32937522 T>C  ·  GRCh38: chr13:32363385 T>C
Gene: BRCA2 Transcript: NM_000059.4
Final call
Likely Benign
BS3 strong BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Val2728Ala)
gnomAD AF
2.4782041941127782e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Likely Neutral
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_000059.4:c.8183T>C (p.Val2728Ala) is a missense variant in exon 18 of BRCA2, located within the DNA binding domain (aa 2481-3186).
2
This variant is present at extremely low frequency in population databases: gnomAD v2.1 (1/31,400 alleles, exclusively in genomes; exome not covered) and gnomAD v4.1 (4/1,614,072 alleles, grpmax FAF=1.746e-05). It is absent from gnomAD-Canada v1.0.
3
In ClinVar (Variation ID 141399), this variant is classified as Uncertain Significance by seven clinical laboratories and Likely Benign by one laboratory (criteria provided, single submitter).
4
ENIGMA Specifications Table 9 assigns BS3_Strong based on a calibrated functional study (Richardson et al. 2021, PMID:33609447) demonstrating that V2728A exhibits HDR activity similar to benign control variants.
5
ENIGMA BP4_Supporting is met: the variant is inside the DNA binding domain with no predicted impact via protein change (BayesDel no-AF=0.103, ≤0.18) and no predicted splicing impact (SpliceAI max delta=0.01, ≤0.1).
6
The clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is LR=1.24 based on 1 proband, falling in the neutral zone and providing no evidence for PP4 or BP5.
7
No pathogenic comparator exists at residue Val2728 (c.8182G>A p.Val2728Ile is classified as benign by ENIGMA), so PS1 is not met. PVS1, PM5, and other null-variant criteria are not applicable to this missense substitution.
8
Applying ENIGMA Table 3 combination rules: BS3_Strong (1 Strong Benign) + BP4_Supporting (1 Supporting Benign) meets the likely benign rule [1 Strong (Benign) + 1 Supporting (Benign)]. The total benign evidence is one Strong and one Supporting criterion with no pathogenic criteria met.
Final determination: Per ENIGMA BRCA1/BRCA2 v1.2.0 Table 3, Likely Benign classification is reached when 1 Strong (Benign) criterion and 1 Supporting (Benign) criterion are both met, with no pathogenic criteria met.
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 PVS1 is applicable only to null variants (nonsense, frameshift, canonical splice ±1,2) per ENIGMA BRCA2 specification v1.2. NM_000059.4:c.8183T>C is a missense variant (p.Val2728Ala) and does not qualify.
pvs1_variant_assessment pvs1_gene_context
PS1 Not met No previously classified pathogenic missense variant exists at the same amino acid residue (Val2728). The comparator c.8182G>A p.(Val2728Ile) is classified as benign (IARC Class 1) by the ENIGMA multifactorial analysis (Parsons et al. 2019, PMID:31131967) and assigned no PS3/BS3 code by ENIGMA Table 9.
vcep_humu_40_1557_s001 vcep_specifications_table9_v1_2_2024_11_18
PS2 N/A Not applicable per ENIGMA BRCA2 specification v1.2.
cspec
PS3 Not met ENIGMA Specifications Table 9 assigns BS3 (not PS3) for this variant based on calibrated functional assay data showing protein function similar to benign control variants (PMID:33609447). The functional evidence points toward benign effect, not pathogenic.
vcep_specifications_table9_v1_2_2024_11_18
PS4 Not met No case-control study demonstrates significantly increased prevalence of this variant in affected individuals versus controls. The variant is absent from the ENIGMA ST7 Reference Set and no published PS4-level evidence was identified.
vcep_supplementarytables_v1_2_2024_11_18
PS5 Not met No reputable source has recently reported this variant as pathogenic with unavailable supporting evidence. The variant is classified as VUS in ClinVar and as Likely Neutral by OncoKB.
clinvar oncokb
PM1 N/A Not applicable per ENIGMA BRCA2 specification v1.2.
cspec
PM2 Not met ENIGMA PM2_Supporting requires absence from both gnomAD v2.1 non-cancer exome and v3.1 non-cancer. The variant is present in gnomAD v2.1 genomes (1/31,400 alleles, AF=3.18e-05) and in gnomAD v4.1 (4/1,614,072 alleles, AF=2.48e-06). It is not absent from population controls.
gnomad_v2 gnomad_v4
PM5 N/A ENIGMA repurposes PM5 for protein termination codon (PTC) variants in exons where a different proven pathogenic PTC has been seen. This is a missense variant and does not qualify for PM5_PTC. Classic same-residue missense PM5 is not used in the ENIGMA BRCA2 framework.
pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable per ENIGMA BRCA2 specification v1.2.
cspec
PP1 Not met No cosegregation data available for this variant. No published studies demonstrate variant tracking with disease in multiple affected family members, and no quantitative cosegregation LR has been calculated.
PP2 N/A Not applicable per ENIGMA BRCA2 specification v1.2.
cspec
PP3 Not met ENIGMA PP3 requires BayesDel no-AF score ≥0.30 for missense variants inside a clinically important functional domain (or SpliceAI ≥0.2 for predicted splicing). The variant has BayesDel=0.103 and SpliceAI max delta=0.01, both below PP3 thresholds.
bayesdel spliceai revel
PP4 Not met The clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is LR=1.24 (1 proband), which falls in the neutral zone (>0.48 and <2.08). Per ENIGMA specification, this LR does not provide supporting evidence in either direction.
vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5 N/A Not applicable per ENIGMA BRCA2 specification v1.2.
cspec
BA1 Not met ENIGMA BA1 requires FAF >0.1% (0.001) in gnomAD non-founder populations. The variant has maximum allele frequency of 0.0115% in gnomAD v2.1 African/African American (1/8,710) and grpmax FAF of 1.746e-05 in v4.1, both far below the BA1 threshold.
gnomad_v2 gnomad_v4
BS1 Not met ENIGMA BS1 requires FAF >0.002% in gnomAD v2.1 non-cancer exome or v3.1 non-cancer. The variant is absent from v2.1 exome (not covered, ac=0/an=0), and gnomAD v4.1 grpmax FAF=1.746e-05 (0.00175%) is below the BS1_Supporting threshold of 0.002%. BS1 thresholds are not met.
gnomad_v2 gnomad_v4
BS2 Not met No evidence of this variant observed in a homozygous state in individuals without Fanconi Anemia phenotype. Per ENIGMA Table 8, BS2 requires point assignment based on proband observations; no such data are available.
BS3 Met ENIGMA Specifications Table 9 assigns BS3_Strong for c.8183T>C p.(Val2728Ala) based on a calibrated functional study (Richardson et al. 2021, PMID:33609447) demonstrating that this variant exhibits protein function similar to benign control variants in a homology-directed repair (HDR) assay.
vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447
BS4 Not met No quantitative lack-of-segregation evidence is available. The variant is absent from the ENIGMA ST7 Reference Set and no published studies report non-segregation in affected family members.
vcep_supplementarytables_v1_2_2024_11_18
BP1 N/A ENIGMA BP1_Strong applies to missense variants located OUTSIDE a clinically important functional domain. Residue 2728 is within the BRCA2 DNA binding domain (aa 2481-3186), a clinically important functional domain per ENIGMA specification. BP1 is not applicable.
cspec
BP2 N/A Not applicable per ENIGMA BRCA2 specification v1.2.
cspec
BP3 N/A Not applicable per ENIGMA BRCA2 specification v1.2. BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution.
cspec
PM3 N/A Not applicable. PM3 requires detection in trans with a pathogenic variant for recessive disorders; no such observations exist for this variant and Fanconi Anemia.
cspec
PM4 N/A Not applicable per ENIGMA BRCA2 specification v1.2. PM4 applies to protein-length changes (in-frame deletions/insertions, stop-loss); this is a missense substitution.
cspec
BP4 Met ENIGMA BP4_Supporting applies to missense variants inside a clinically important functional domain with no predicted impact via protein change or splicing: BayesDel no-AF score ≤0.18 AND SpliceAI ≤0.1. This variant satisfies both conditions (BayesDel=0.103, SpliceAI max delta=0.01) and is located within the BRCA2 DNA binding domain (aa 2481-3186).
bayesdel spliceai cspec
BP5 Not met The clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is LR=1.24 (1 proband), which falls in the neutral zone (>0.48 and <2.08). Per ENIGMA specification, this LR does not support BP5 (which requires LR≤0.48 for Supporting).
vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6 N/A Not applicable per ENIGMA BRCA2 specification v1.2.
cspec
BP7 N/A ENIGMA BP7_Supporting applies only to silent variants inside a functional domain (if BP4 met) or intronic variants outside conserved splice motifs. BP7_Strong (RNA) requires mRNA assay evidence showing no damaging effect on splicing. This is a missense variant inside the DNA binding domain with no mRNA assay data available; BP7 is not applicable.
cspec
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