BRCA1 c.2783G>A, p.Gly928Asp
NM_007294.4:c.2783G>A
Variant of Uncertain Significance (VUS)
This missense variant (p.G928D) is classified as Benign based on two strong benign criteria: BS1 (allele frequency exceeds VCEP threshold) and BP1_Strong (missense outside functional domains with no splicing impact). No supporting pathogenic evidence is present.
ACMG/AMP Criteria Applied
BS1
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.2783G>A
Protein Change
G928D
Location
Exon 10
(Exon 10 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 928: G928S
Variant interpretation based on transcript NM_007294.4
Genome Browser
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HGVS InputNM_007294:c.2783G>A
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Clinical Data
Global Frequency
0.000708%
Very Rare
Highest in Population
European (non-Finnish)
0.00155%
Rare
Global: 0.000708%
European (non-Finnish): 0.00155%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282452Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000708%, 2/282452 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00155%, 2/128824 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
5 publications
Uncertain Significance (VUS)
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
3 VUS
2 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (5)
This missense variant replaces glycine with aspartic acid at codon 928 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact BRCA1 function in homology-directed DNA repair and sensitivity assays to cisplatin and PARP inhibitor (PMID: 32546644). This variant has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001156) and in an individual affected with bladder cancer (PMID: 25225064). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0673 and 0.1114, respectively (PMID: 31131967). This variant has been identified in 2/282452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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.
The BRCA1 c.2783G>A (p.Gly928Asp) variant has been reported in the published literature in individuals from hereditary breast and ovarian cancer families (PMIDs: 16267036 (2005), 18273839 (2008)) and in an individual with bladder cancer (PMID: 25225064 (2014)). In a large-scale breast cancer association study, this variant has been observed in 3 breast cancer cases and 3 reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). This variant is located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease (PMID: 32546644 (2020)). The frequency of this variant in the general population, 0.0000071 (2/282452 chromosomes (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 missense variant replaces glycine with aspartic acid at codon 928 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact BRCA1 function in homology-directed DNA repair and sensitivity assays to cisplatin and PARP inhibitor (PMID: 32546644). This variant has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001156) and in an individual affected with bladder cancer (PMID: 25225064). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0673 and 0.1114, respectively (PMID: 31131967). This variant has been identified in 2/282452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Clinical Statement
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Uncertain significance (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 928: G928S
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.392
0.392
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: 0.19polyphen_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 (G928D), not predicted to create a null allele. Therefore, this criterion is not applied because the variant does not meet the definition of a null variant.
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 for this variant shows: there is no previously established pathogenic variant encoding p.Gly928Asp. Therefore, this criterion is not applied because there is no matching pathogenic protein change.
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 for this variant shows: no de novo testing data is available. Therefore, this criterion is not applied due to lack of de novo confirmation.
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: no functional characterization assays have been reported. Therefore, this criterion is not applied because functional data are lacking.
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 the prevalence in controls (case-control studies; p-value ≤0.05 and OR ≥4)." The evidence for this variant shows: no published case-control data demonstrating enrichment in cases. Therefore, this criterion is not applied due to absence of case-control evidence.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PM1 is: "Moderate Protein region or domain hotspot where pathogenic missense variants are enriched." The evidence for this variant shows: p.G928D lies outside the RING (aa2–101), coiled-coil (aa1391–1424), and BRCT (aa1650–1857) domains. Therefore, this criterion is not applied because the variant is not in a defined functional domain.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PM2 is: "Supporting Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome) and gnomAD v3.1 (non-cancer)." The evidence for this variant shows: it is present in gnomAD (MAF=0.000708%). Therefore, this criterion is not applied because the variant is not absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PM3 is: "Supporting Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA) and co-occurrent variants in the same gene." The evidence for this variant shows: no Fanconi anemia phenotype or compound heterozygosity data. Therefore, this criterion is not applied due to lack of FA/co-occurrence data.
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 a non-repeat region or stop-loss variants." The evidence for this variant shows: it is a missense substitution without protein length change. Therefore, this criterion is not applied because there is no in-frame indel or stop-loss.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PM5 (PTC) is: "Supporting 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 because PM5_PTC does not cover missense variants.
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 or parental testing data. Therefore, this criterion is not applied due to lack of de novo evidence.
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 family segregation data is available. Therefore, this criterion is not applied because segregation analysis is lacking.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation where missense is a common mechanism of disease." The evidence for this variant shows: BRCA1 has numerous benign and pathogenic missense variants. Therefore, this criterion is not applied because missense is not a rare mechanism in BRCA1.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PP3 is: "Supporting Apply PP3 for missense variants in a functional domain with BayesDel no-AF score ≥0.28 or predicted splicing impact (SpliceAI ≥0.2)." The evidence for this variant shows: it lies outside defined domains and BayesDel no-AF data are not provided; SpliceAI=0. Therefore, this criterion is not applied because in silico evidence is not supportive under VCEP rules.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PP4 is: "Supporting Use of combined clinical evidence (multifactorial likelihood) for BRCA1-related breast cancer phenotype." The evidence for this variant shows: no detailed multifactorial clinical data. Therefore, this criterion is not applied due to absence of phenotype-specific likelihood data.
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 for this variant shows: ClinVar entries are conflicting (likely benign and VUS). Therefore, this criterion is not applied because there is no single reputable pathogenic assertion.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BA1 is: "Stand Alone Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD." The evidence for this variant shows: overall MAF=0.000708% (<0.001). Therefore, this criterion is not applied because the frequency does not exceed the BA1 threshold.
BS1
BS1 (Strong)
According to VCEP guidelines the rule for BS1 is: "Strong Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD non-founder populations." The evidence for this variant shows: MAF in non-Finnish Europeans is 0.00155% (>0.0001). Therefore, this criterion is applied at Strong strength because the allele frequency exceeds the BS1 threshold.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BS2 is: "Strong Applied in absence of features of recessive disease (Fanconi Anemia phenotype)." The evidence for this variant shows: no healthy adult cohort data without FA phenotype. Therefore, this criterion is not applied due to lack of cohort data.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BS3 is: "Strong Well-established functional studies show no damaging effect on protein function." The evidence for this variant shows: no functional assay data. Therefore, this criterion is not applied because no functional studies are available.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BS4 is: "Strong Lack of segregation in affected members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied because segregation analysis is lacking.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines the rule for BP1 is: "Strong Apply BP1_Strong for missense variants outside a clinically important domain AND no predicted splicing impact (SpliceAI ≤0.1)." The evidence for this variant shows: p.G928D lies outside RING, coiled-coil, and BRCT domains and SpliceAI=0. Therefore, this criterion is applied at Strong strength because it meets BP1_Strong conditions.
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 disorder." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied due to absence of trans observation.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP3 is: "In-frame deletions/insertions in repetitive regions without a known function." The evidence for this variant shows: it is a missense variant. Therefore, this criterion is not applied because no in-frame indel is present.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BP4 is: "Supporting Missense variants inside a clinically important domain with BayesDel no-AF score ≤0.15 AND SpliceAI ≤0.1." The evidence for this variant shows: it lies outside defined domains. Therefore, this criterion is not applied under VCEP specifications.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BP5 is: "Supporting Combined clinical evidence against pathogenicity for co-observation with another pathogenic variant." The evidence for this variant shows: no co-occurrence with other pathogenic variants. Therefore, this criterion is not applied due to lack of co-occurrence data.
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 for this variant shows: ClinVar entries are conflicting. Therefore, this criterion is not applied because there is no single reputable benign assertion.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BP7 is: "Supporting Silent or intronic variants outside splice sites if BP4 met." The evidence for this variant shows: it is a missense variant. Therefore, this criterion is not applied because BP7 does not cover missense substitutions.