BRCA2 c.3497T>A, p.Val1166Asp
NM_000059.4:c.3497T>A
Variant of Uncertain Significance (VUS)
This missense variant (V1166D) lies outside BRCA2 functional domains, has no functional or segregation data, and is extremely rare but present in population databases. Only BP1_Strong applies. Insufficient evidence for pathogenic or benign classification; remains VUS.
ACMG/AMP Criteria Applied
BP1
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.3497T>A
Protein Change
V1166D
Location
Exon 11
(Exon 11 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 1166: V1166I, V1166A
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.3497T>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000399%
Extremely Rare
Highest in Population
European (non-Finnish)
0.000883%
Very Rare
Global: 0.000399%
European (non-Finnish): 0.000883%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250862Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000399%, 1/250862 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.000883%, 1/113234 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
3 publications
Uncertain Significance (VUS)
Based on 7 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
3 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
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.
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Clinical Statement
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Uncertain significance (4 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 1166: V1166I, V1166A
PM5 criterion applied.
Functional Summary
The BRCA2 V1166D variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.338
0.338
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: -0.51polyphen_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: "Very Strong Null variant...". The evidence for this variant shows a missense change (V1166D), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Same amino acid change as a previously established pathogenic variant...". The evidence for this variant shows no previously established pathogenic variant at codon V1166. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "De novo (both maternity and paternity confirmed)...". No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Well-established in vitro or in vivo functional studies supportive of a damaging effect...". No functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "The prevalence of the variant in affected individuals is significantly increased compared to controls...". No case-control data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: PM1 applies to variants in mutational hotspots or functional domains (BRCA2 aa 10-40, 2481-3186). Codon 1166 lies outside these regions. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines: "PM2_Supporting: Absent from controls...". The variant is present in gnomAD at MAF 0.000399%. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: PM3 applies for BRCA2-related Fanconi Anemia co-occurrence. No FA phenotype or co-occurrence data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Protein length changing variant...". This is a missense change, not a length-altering variant. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: PM5 applies only to protein termination codon variants. This variant is missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PM6: Assumed de novo without confirmation...". No de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: "PP1: Co-segregation with disease in multiple affected family members...". No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP2: Missense variant in gene with low rate of benign missense variation...". BRCA2 does not meet this gene property. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: "PP3: Predicted splicing impact (SpliceAI ≥0.2) or missense in functional domain (BayesDel ≥0.30)...". SpliceAI ≤0.1 and codon 1166 is outside known functional domains. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines: "PP4: Patient phenotype or family history specific to BRCA2-related disease...". No phenotype data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP5: Reputable source reports variant as pathogenic...". ClinVar submissions are conflicting. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: "BA1: FAF >0.1%...". MAF 0.000399% < threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: "BS1: FAF >0.01%...". MAF 0.000399% < threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: "BS2: Observed in healthy adults without FA phenotype...". No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: "BS3: Well-established functional studies show no damaging effect...". No functional data are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: "BS4: Lack of segregation in affected family members...". No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines: "BP1_Strong: Missense variant outside a clinically important functional domain AND no splicing impact predicted (SpliceAI ≤0.1)." The variant V1166D lies outside BRCA2 domains (aa 10-40, 2481-3186) and SpliceAI ≤0.1. Therefore, this criterion is applied at Strong strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP2: Observed in trans with a pathogenic variant...". No data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP3: In-frame indel in repetitive region...". This is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: "BP4: Missense in functional domain with no predicted impact...". Variant lies outside functional domains. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines: "BP5: Co-occurrence with pathogenic variant in another gene...". No such data are available. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP6: Reputable source reports variant as benign...". ClinVar submissions are conflicting. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: "BP7: Silent or intronic variant...". This is a missense change. Therefore, this criterion is not applied.