BRCA2 c.8686C>T, p.Arg2896Cys
NM_000059.4:c.8686C>T
COSMIC ID: COSM1184868
Variant of Uncertain Significance (VUS)
The variant c.8686C>T (p.R2896C) in BRCA2 is classified as VUS due to application of PM5 (Moderate) based on a known pathogenic missense at the same residue, PM2 (Supporting) for extreme rarity, and BP4 (Supporting) for benign computational predictions, which together are insufficient to meet criteria for pathogenic or benign classification.
ACMG/AMP Criteria Applied
PM2
PM5
BP4
Genetic Information
Gene & Transcript Details
Gene
BRCA2
Transcript
NM_000059.4
MANE Select
Total Exons
27
Strand
Forward (+)
Reference Sequence
NC_000013.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000059.2 | Alternative | 27 exons | Forward |
| NM_000059.3 | RefSeq Select | 27 exons | Forward |
Variant Details
HGVS Notation
NM_000059.4:c.8686C>T
Protein Change
R2896C
Location
Exon 21
(Exon 21 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 2896: R2896S, R2896L, R2896H
Alternate Identifiers
COSM1184868
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.8686C>T
Active Tracks
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Clinical Data
Global Frequency
0.00199%
Rare
Highest in Population
South Asian
0.0163%
Low Frequency
Global: 0.00199%
South Asian: 0.0163%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251298Alt: 5Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00199%, 5/251298 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.0163%, 5/30608 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
4 publications
Uncertain Significance (VUS)
Based on 14 submitter reviews in ClinVar
Submitter Breakdown
11 VUS
3 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
This 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.
Clinical Statement
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).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 2896: R2896S, R2896L, R2896H
PM5 criterion applied.
Functional Summary
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.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.248
0.248
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.73polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
PS3 (Not Applied) Strength Modified
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
PS4 (Not Applied) Strength Modified
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
PM1 (Not Applied) Strength Modified
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
PM2 (Supporting) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
PM4 (Not Applied) Strength Modified
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
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
PM6 (Not Applied) Strength Modified
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
PP1 (Not Applied) Strength Modified
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
PP2 (Not Applied) Strength Modified
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
PP3 (Not Applied) Strength Modified
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
PP4 (Not Applied) Strength Modified
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
PP5 (Not Applied) Strength Modified
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
BA1 (Not Applied) Strength Modified
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
BS1 (Not Applied) Strength Modified
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
BS2 (Not Applied) Strength Modified
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
BS3 (Not Applied) Strength Modified
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
BS4 (Not Applied) Strength Modified
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
BP1 (Not Applied) Strength Modified
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
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
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
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
BP7 (Not Applied) Strength Modified
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.