BRCA2 c.8507C>G, p.Ser2836Cys
NM_000059.4:c.8507C>G
Variant of Uncertain Significance (VUS)
This variant remains of uncertain significance because only two moderate (PM5) and two supporting (PM2, BP4) criteria are met, which is insufficient for a Likely Pathogenic or Benign classification. Additional functional studies, segregation, or case-control data are needed to resolve its clinical impact.
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.8507C>G
Protein Change
S2836C
Location
Exon 20
(Exon 20 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 2836: S2836P
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.8507C>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Uncertain Significance (VUS)
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (3 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 2836: S2836P
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.232
0.232
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
Pathogenic:
polyphen_prediction: probably_damaging
Benign:
CADD: 4.29metasvm: 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, PVS1 applies to null variants in BRCA2 where loss of function is known mechanism. NM_000059.4:c.8507C>G is a missense variant, not a null variant. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a variant results in the same amino acid change as a previously established pathogenic variant. There is no evidence of a previously established pathogenic variant causing S2836C. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires confirmation of de novo occurrence with parental identity confirmed. No parental testing or de novo evidence is available. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 requires well-established functional studies showing a damaging effect. No functional assays have been performed on this variant. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires statistically significant increased prevalence in affected individuals compared to controls. No case-control or cohort data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants located in a mutational hotspot or critical functional domain without benign variation. Although the variant lies within the BRCA2 DNA binding domain (aa 2481–3186), there is insufficient evidence that this position is a mutational hotspot. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2_Supporting: "Absent from controls in an outbred population, from gnomAD v2.1 and v3.1." The variant is not observed in gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 requires evidence of trans configuration with a pathogenic variant in a patient with Fanconi anemia phenotype. No such phenotype or co-occurrence data are available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels or stop-loss). This missense variant does not change protein length. Therefore, PM4 is not applied.
PM5
PM5 (Moderate)
According to standard ACMG guidelines, PM5_Moderate: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen." A different pathogenic missense at residue S2836 has been reported. Therefore, PM5 is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without confirmation. Parental testing data are unavailable. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires co-segregation data in affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies when missense variants in a gene with low rate of benign missense variation are observed. BRCA2 has a high rate of reported missense variants and no evidence supports a low benign variation rate at this position. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3_Supporting requires BayesDel no-AF ≥0.30 and predicted impact via protein change for missense in a functional domain. BayesDel no-AF score is not available and in silico predictions are mixed. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 requires specific phenotype data and multifactorial likelihood evidence. No detailed clinical phenotype or multifactorial data are available. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source reports the variant as pathogenic. ClinVar classifies this variant as Uncertain Significance. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies when allele frequency is >0.1% in gnomAD. The variant is absent (MAF=0%). Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies when allele frequency is >0.01%. The variant is absent in population databases. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies when variant observed in healthy adult individuals inconsistent with disease expectation. No such observations exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires functional studies showing no damaging effect. No functional assays are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in families. No segregation studies have been performed. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 applies to missense variants outside clinically important domains with no predicted splicing impact. This variant is within the DNA binding domain. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when variant found in trans with a pathogenic variant in autosomal dominant disease. No trans observations are reported. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a missense SNV, not an indel. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4_Supporting: "Missense variants inside a functional domain with no predicted impact via protein change (BayesDel no-AF ≤0.18) and splicing (SpliceAI ≤0.1)." SpliceAI predicts no splicing impact (0.01) and in silico predictors overall favor benign. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternate genetic explanation. No such co-occurrence data are available. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source reports a variant as benign without supporting evidence. No such assertions exist. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to silent or intronic variants with no splicing impact. This is a missense variant. Therefore, BP7 is not applied.