The BRCA2 c.7961T>C (p.Leu2654Pro) variant has been reported in ClinVar with an expert-panel classification of uncertain significance and mixed submitter assertions.1 This variant is present at very low frequency in population databases, including 1/31,406 alleles in gnomAD v2.1 and 3/1,614,066 alleles in gnomAD v4.1, which argues against PM2 and does not reach BA1 or BS1 thresholds.2 In the ENIGMA BRCA2 curated functional dataset, this variant has discordant calibrated assay results, so the available functional evidence does not support either PS3 or BS3.3 Computational evidence supports a damaging protein effect because the variant lies in the BRCA2 DNA-binding domain, BayesDel no-AF is 0.314702 above the PP3 threshold of 0.30, REVEL is 0.82, and SpliceAI predicts no significant splice effect with a max delta score of 0.02.4
Final classification
Uncertain Significance
PP3
BRCA2
c.7961T>C
p.Leu2654Pro
This variant
The BRCA2 c.7961T>C (p.Leu2654Pro) variant has been reported in ClinVar with an expert-panel classification of uncertain significance and mixed submitter assertions.
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/VCEP primary authority).
Classification rationale
PP3
Uncertain Significance
BRCA2 c.7961T>C
PP3
→
Uncertain Significance
3
vcep_specifications_table9_v1_2_2024_11_18PMID:29884841 ↗
4
cspec ↗bayesdelrevelspliceai ↗
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_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 16 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
PP3
supporting
review
Pathogenic
This missense variant lies within the BRCA2 DNA-binding domain (aa 2481-3186). BayesDel no-AF is 0.314702, which is above the ENIGMA PP3 threshold of ≥0.30, REVEL is 0.82, and SpliceAI predicts no significant splice effect (max delta 0.02), supporting a damaging protein effect; therefore PP3 is met at supporting strength.
BayesDel no-AF 0.314702.REVEL 0.82.SpliceAI max delta 0.02.
Assessed · not applied
· 10 not met · 6 not assessed
Pathogenic
PVS1
This variant is a missense substitution, not a nonsense, frameshift, or canonical ±1/2 splice-site variant, and no RNA evidence showing an abnormal loss-of-function transcript was identified.
PS1
No verified evidence was identified showing that this variant produces the same pathogenic amino-acid change or the same pathogenic splicing effect as a previously classified pathogenic or likely pathogenic BRCA2 variant, so PS1 was not assessed.
PS3
In the ENIGMA BRCA2 functional table, this variant is summarized as having discordant results across two or more calibrated studies.
PS4
No case-control study, odds ratio, or quantitative enrichment data were identified showing this variant is significantly more common in affected individuals than in controls, so PS4 was not assessed.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified showing this variant in trans with another pathogenic BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 was not assessed.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.
PP4
The BRCA2 clinical-history likelihood ratio for this variant is 1.4293 in 2 probands.
Benign
BA1
Available population data do not reach the BA1 threshold.
BS1
Available population data do not reach the BS1 thresholds.
BS2
No qualifying observations were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA BS2 scoring framework, so BS2 was not assessed.
BS3
In the ENIGMA BRCA2 functional table, this variant is summarized as having discordant results across calibrated studies rather than a consistent normal-function result.
BS4
No quantitative non-segregation data were identified for this variant, so BS4 was not assessed.
BP1
BP1_Strong in the ENIGMA BRCA2 specification applies to missense variants outside clinically important domains with no predicted splice effect.
BP4
Although SpliceAI predicts no significant splice impact (max delta 0.02), this missense variant is in the BRCA2 DNA-binding domain and BayesDel no-AF is 0.314702, which is above the BP4 requirement of ≤0.18.
BP5
The BRCA2 clinical-history likelihood ratio for this variant is 1.4293 in 2 probands.
N/A · 11
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.85866e-06; MAF= 0.00019%, 3/1614066 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.66894e-05; MAF= 0.00267%, 2/74936 alleles, homozygotes = 0); grpmax FAF= 4.43e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.1841e-05; MAF= 0.00318%, 1/31406 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114784; MAF= 0.01148%, 1/8712 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,614,066
0 hom · FAF 0.00044%
0 hom · FAF 0.00044%
African/African American 2 / 74,936 |
0.0027% |
European (non-Finnish) 1 / 1,180,048 |
8.5e-05% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0032%
· 1 / 31,406
0 hom
0 hom
African/African American 1 / 8,712 |
0.011% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 52448)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.82. BayesDel score = 0.314702.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
29394989 ↗
Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches.
ONCOKB
35736817 ↗
Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay.
ONCOKB
23108138 ↗
A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity.
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
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR