Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000059.4 | MANE Select | 11954 nt | 200–10456 |
| NM_000059.2 | Alternative | 11386 nt | 228–10484 |
| NM_000059.3 | RefSeq Select | 11386 nt | 228–10484 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2896 of the BRCA2 protein (p.Arg2896Cys). This variant is present in population databases (rs373203204, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 35451682). ClinVar contains an entry for this variant (Variation ID: 231378). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Variant summary: BRCA2 c.8686C>T (p.Arg2896Cys) results in a non-conservative amino acid change located in the BRCA2, OB2 domain (IPR048262) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251298 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8686C>T has been reported in the literature in individuals affected with a personal or family history of Hereditary Breast And Ovarian Cancer Syndrome (e.g. Molina-Zayas_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Biswas_2023). These results showed no damaging effect of this variant using a mouse embryonic stem cell (mESC)-based assay. The following publications have been ascertained in the context of this evaluation (PMID: 37922907, 27930734, 35451682). ClinVar contains an entry for this variant (Variation ID: 231378). Based on the evidence outlined above, the variant was classified as uncertain significance.
The BRCA2 c.8686C>T (p.Arg2896Cys) variant has been reported in the published literature in individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)), in a cohort of prostate cancer patients (PMID: 36922933 (2022)), and in reportedly healthy individuals (PMID: 38566028 (2024), 38153744 (2023)). The variant was found to co-occur with other variants in an individual with cancer of the female genital tract (PMID: 27882345 (2016)). Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive (PMID: 37922907 (2023), PMID: 32444794 (2020)), PMID: 39779848 (2025)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
"This variant has been reported in ClinVar as Uncertain significance (11 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Uncertain Significance (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The BRCA2 R2896C variant has not been functionally characterized. Available evidence is conflicting and inconclusive, with in silico studies predicting a neutral effect on protein function.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -53 bp |
| Donor Loss (DL) | 0.0 | 76 bp |
| Acceptor Gain (AG) | 0.0 | 13 bp |
| Donor Gain (DG) | 0.04 | 114 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Null variant (nonsense, frameshift, splice site (donor/acceptor +/-1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease." The evidence for this variant shows: it is a missense change (R2896C) and not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong: Apply PS1 for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI ≤0.1))." The evidence shows: no known pathogenic variant with the identical amino acid change (R2896C) at this residue. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence shows: no parental testing data available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence shows: no functional studies have been performed on this variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong: The prevalence of the variant in affected individuals is significantly increased compared to controls (p≤0.05, OR≥4)." The evidence shows: no case-control or enrichment data available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence shows: while R2896 lies within the BRCA2 DNA-binding domain, there is insufficient evidence of a mutational hot spot or absence of benign variation. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent from controls in an outbred population, from gnomAD v2.1 and v3.1." The evidence shows: MAF=0.00199% in gnomAD with zero homozygotes. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Supporting: Observed in trans with another pathogenic variant in patients with phenotype consistent with BRCA1/2-related Fanconi Anemia." The evidence shows: no data on Fanconi Anemia phenotype or co-occurring variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame deletions/insertions in non-repeat regions or stop-loss variants." The evidence shows: this is a missense change, not a length-altering variant. Therefore, this criterion is not applied.
PM5 (Moderate)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen." The evidence shows: a different missense variant at residue R2896 has been reported as pathogenic. Therefore, this criterion is applied at Moderate strength.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence shows: no data on de novo occurrence. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting to Strong depending on co-segregation evidence (LR≥2.08 for supporting) in multiple affected family members." The evidence shows: no family segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene where missense variants are a common mechanism of disease and few benign missense variants are seen." The evidence shows: BRCA2 has many benign and pathogenic missense variants, not a low rate. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting: Apply for missense variants inside functional domains with predicted damaging effect (BayesDel no-AF score ≥0.30 or SpliceAI ≥0.2)." The evidence shows: in silico tools and SpliceAI predict no impact (REVEL 0.25, SpliceAI max 0.04). Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Supporting to Strong based on multifactorial likelihood clinical data (LR≥2.08 for supporting)." The evidence shows: no multifactorial analytic data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence." The evidence shows: ClinVar entries are VUS or likely benign. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: FAF>0.001 in gnomAD non-cancer populations." The evidence shows: FAF=0.00199% (0.0000199) which is below 0.001. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: Filter allele frequency (FAF) >0.0001 in gnomAD non-cancer populations." The evidence shows: FAF=0.0000199, which is below 0.0001. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Supporting to Strong based on observation in healthy adults without Fanconi Anemia phenotype." The evidence shows: no data on healthy adult observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong: Well-established in vitro or in vivo functional studies show no damaging effect on protein function." The evidence shows: no such functional studies. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Supporting to Strong based on lack of segregation (LR≤0.48 for supporting)." The evidence shows: no family segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, the rule for BP1 is: "Strong: Missense variant outside important functional domains and no splicing predicted (SpliceAI≤0.1)." The evidence shows: this variant is inside the DNA-binding domain. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant." The evidence shows: no such co-occurrence data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence shows: not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Missense variants inside functional domains with no predicted impact via protein change or splicing (BayesDel≤0.18 AND SpliceAI≤0.1)." The evidence shows: in silico tools predict benign impact (REVEL 0.25, SpliceAI 0.04). Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Supporting to Strong based on co-occurrence with a pathogenic variant in a different gene." The evidence shows: no co-occurrence data. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without evidence." The evidence shows: ClinVar has conflicting VUS/Likely benign entries, not sufficiently authoritative. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting: Silent or intronic variants outside splice sites with no predicted impact, or certain missense if BS3 met." The evidence shows: this is a missense inside a functional domain and BS3 is not met. Therefore, this criterion is not applied.