BRCA1 c.2083G>A, p.Asp695Asn
NM_007294.4:c.2083G>A
COSMIC ID: COSM6965200
Variant of Uncertain Significance (VUS)
This BRCA1 D695N variant is classified as Likely Benign based on strong functional evidence of no impact (BS3) and strong location-based evidence outside key domains (BP1), supported by an extremely low population frequency (PM2).
ACMG/AMP Criteria Applied
PM2
BS3
BP1
Genetic Information
Gene & Transcript Details
Gene
BRCA1
Transcript
NM_007294.4
MANE Select
Total Exons
23
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_007294.2 | Alternative | 23 exons | Reverse |
| NM_007294.3 | RefSeq Select | 23 exons | Reverse |
Variant Details
HGVS Notation
NM_007294.4:c.2083G>A
Protein Change
D695N
Location
Exon 10
(Exon 10 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 695 in gene BRCA1
Alternate Identifiers
COSM6965200
Variant interpretation based on transcript NM_007294.4
Genome Browser
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HGVS InputNM_007294:c.2083G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00319%
Rare
Highest in Population
Remaining individuals
0.0277%
Low Frequency
Global: 0.00319%
Remaining individuals: 0.0277%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282558Alt: 9Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00319%, 9/282558 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0277%, 2/7212 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
7 publications
Uncertain Significance (VUS)
Based on 12 submitter reviews in ClinVar
Submitter Breakdown
6 VUS
5 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (7)
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 695 of the BRCA1 protein (p.Asp695Asn). This variant is present in population databases (rs28897681, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9523200, 31907386). ClinVar contains an entry for this variant (Variation ID: 54455). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 23867111, 26689913, 32546644). 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.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Benign (1 clinical laboratories) and as Likely benign (5 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
No evidence of other pathogenic variants at position 695 in gene BRCA1
Functional Summary
The BRCA1 D695N variant has been functionally characterized and is suggested to be likely neutral based on its response to cisplatin treatment.
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
0.248
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: 1.17metasvm: 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 (+/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: it is a missense change (D695N), 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 results in the same amino acid change.' The evidence for this variant shows: no previously established pathogenic variant results in the same D695N amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (paternity and maternity confirmed) in a patient with the disease and no family history.' The evidence for this variant shows: no data on de novo occurrence. 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 for this variant shows: functional assay (cisplatin response) indicates a likely neutral effect on protein function. 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 (case-control with p≤0.05 and OR≥4).' The evidence for this variant shows: no case-control or prevalence data in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate Applies to variants located in a mutational hot spot or well‐studied functional domain without benign variation.' The evidence for this variant shows: D695N is located outside the defined clinically important functional domains (RING 2-101, coiled-coil 1391-1424, BRCT 1650-1857). Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 (Supporting) is: 'Absent from controls in an outbred population, from gnomAD v2.1 and v3.1.' The evidence for this variant shows: MAF = 0.00319% in gnomAD (9/282,558 alleles), extremely low frequency. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: 'Supports pathogenicity for variants observed in trans with a pathogenic variant in recessive disorders with a consistent phenotype.' The evidence for this variant shows: no data on trans observations in Fanconi Anemia patients. 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 due to in-frame deletions/insertions in non-repeat regions.' The evidence for this variant shows: it is a missense substitution without change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Moderate Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before.' The evidence for this variant shows: it is a missense change, not a PTC. Therefore, this criterion is not applied.
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 for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no 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 with low rate of benign missense variation and where missense is a common mechanism of disease.' The evidence for this variant shows: insufficient data to establish that missense is a common mechanism for pathogenic variants at this position. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting Apply PP3 for missense or in-frame variants inside a clinically important functional domain with predicted impact via protein change (BayesDel no-AF ≥0.28) or splicing (SpliceAI ≥0.2).' The evidence for this variant shows: BayesDel no-AF <0.28, SpliceAI ≤0.1, and no predicted impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: 'Supporting Breast cancer is common; apply only to multifactorial likelihood clinical data (LR ≥2.08).' The evidence for this variant shows: no multifactorial likelihood 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.' The evidence for this variant shows: ClinVar submissions are mostly 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 if filter allele frequency (FAF) >0.1% in gnomAD non-founder populations.' The evidence for this variant shows: FAF = 0.00319%, below the BA1 threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong if FAF >0.01% and ≤0.1% in gnomAD non-founder populations.' The evidence for this variant shows: FAF = 0.00319%, below the BS1 threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Support against recessive disease when variant observed in healthy individuals (Fanconi Anemia phenotype absent).' The evidence for this variant shows: no data on healthy adult observations with absence of FA phenotype. Therefore, this criterion is not applied.
BS3
BS3 (Strong)
According to VCEP guidelines, BS3 (Strong) is: 'Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.' The evidence for this variant shows: functional assay (cisplatin response) indicates likely neutral effect on BRCA1 function. Therefore, this criterion is applied at Strong strength.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Strong Lack of segregation in affected members of a family.' The evidence for this variant shows: no segregation analysis. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines, BP1_Strong is: 'Apply BP1_Strong for missense variants outside a clinically important functional domain and no splicing predicted (SpliceAI ≤0.1).' The evidence for this variant shows: D695N lies outside RING (2-101), coiled-coil (1391-1424), and BRCT (1650-1857) domains, and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Strong strength.
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 gene.' The evidence for this variant shows: no 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 indels in repetitive regions without a known function.' The evidence for this variant shows: it is a missense substitution, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 applies only to missense or in-frame variants inside a clinically important functional domain with no predicted impact. The evidence for this variant shows: D695N is outside clinically important domains. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 is: 'Supporting for combined LR against pathogenicity based on multifactorial likelihood clinical data (co-occurrence with another pathogenic variant without specific phenotype).' The evidence for this variant shows: no such 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.' The evidence for this variant shows: ClinVar submissions include uncertain or conflicting interpretations. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to intronic or silent variants outside conserved splice motifs with no impact. The evidence for this variant shows: it is a missense substitution. Therefore, this criterion is not applied.