BRCA1 c.131G>A, p.Cys44Tyr
NM_007294.4:c.131G>A
COSMIC ID: COSM10284902
Likely Pathogenic
This legacy system is being phased out as Project HERA V3 is rolled out.
ACMG/AMP Criteria Applied
PS3
PM2
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.131G>A
Protein Change
C44Y
Location
Exon 3
(Exon 3 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 44 in gene BRCA1
Alternate Identifiers
COSM10284902
Variant interpretation based on transcript NM_007294.4
Genome Browser
Loading genome browser...
HGVS InputNM_007294:c.131G>A
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
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
7 publications
Pathogenic
Based on 10 submitter reviews in ClinVar
Submitter Breakdown
9 Path
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (7)
The BRCA1 c.131G>A (p.Cys44Tyr) variant has been reported in the published literature in individuals with ovarian cancer (PMID: 36367610 (2023), 31825140 (2019)) and breast cancer (PMID: 27083775 (2016)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 21922593 (2011), 25823446 (2015), 27272900 (2016), 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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 damaging. Based on the available information, this variant is classified as pathogenic.
This submission and the accompanying classification are no longer maintained by the submitter.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.
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
The p.C44Y variant (also known as c.131G>A), located in coding exon 2 of the BRCA1 gene, results from a G to A substitution at nucleotide position 131. The cysteine at codon 44 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration, along with another alteration, p.C44S, at the same position, has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8; Lindor NM et al. Hum. Mutat., 2012 Jan;33:8-21). This alteration was shown to disrupt the function of the protein in multiple functional studies using different assays (Millot GA et al. Hum. Mutat., 2011 Dec;32:1470-80; Starita LM et al. Genetics, 2015 Jun;200:413-22; Thouvenot P et al. PLoS Genet., 2016 Jun;12:e1006096). In addition, a recent study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562(7726):217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (9 clinical laboratories) and as pathogenic (1 clinical laboratories) and as Uncertain significance (1 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel.
Expert Panel Reviews
Pathogenic
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
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 44 in gene BRCA1
Functional Summary
The BRCA1 C44Y variant has been functionally characterized and shown to have a damaging effect. It promotes cell colony growth in a yeast-based assay and disrupts the binding of BRCA1 to the E2 ubiquitin-conjugating enzyme UbcH5a, indicating a potential oncogenic role. However, the requirement of E3 ligase activity for BRCA1 tumor suppression remains unclear.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 5.51
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 is for null variants (nonsense, frameshift, canonical ±1–2 splice sites, initiation codon) in a gene where loss of function is a known mechanism. This is a missense change (C44Y). Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 is for a missense change that results in the same amino acid change as a known pathogenic variant with no predicted splicing impact. No other variant at codon 44 has been classified as pathogenic. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence. No parental testing or de novo data are available. Therefore, PS2 is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, PS3 (Strong) is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect." The BRCA1 C44Y variant has been shown in a yeast colony growth assay to promote cell growth and in binding assays to disrupt BRCA1–UbcH5a interaction. Therefore, PS3 is applied at Strong strength.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 (Strong) requires case–control data demonstrating a significant increase in affected individuals (OR ≥4, p≤0.05). No case–control or prevalence data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to variants in mutational hot spots or well-established functional domains with enrichment of pathogenic variants. Although C44Y lies in the RING domain (aa 2–101), there is no evidence that codon 44 is a hotspot distinct from general domain context. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 (Supporting) is: "Absent from controls in gnomAD v2.1 and v3.1 non-cancer populations with adequate coverage." The C44Y variant is absent from gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to biallelic variants in trans in individuals with BRCA1-related Fanconi anemia. No phenotype or trans-observation 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, stop-loss). This is a missense substitution. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 applies when a different amino acid change at the same residue is known to be pathogenic. No other missense at codon 44 is documented as pathogenic. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo cases without confirmation. No de novo or parental data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires segregation data in multiple 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 for missense variants in a gene with low benign missense rate and where missense are a common disease mechanism. BRCA1 has many missense VUS and does not meet PP2 criteria. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 (Supporting) requires BayesDel no-AF ≥0.28 or SpliceAI ≥0.2. The available in silico data (CADD 5.5, SpliceAI 0.01) do not meet these thresholds. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies for phenotype specificity and multifactorial likelihood evidence. No detailed clinical phenotype or likelihood modeling is available. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 is for reputable source assertions without available evidence. Given direct functional and population data are available, PP5 is not applied per SVI recommendations.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 (Stand Alone) requires allele frequency >0.1% in gnomAD. The variant is absent. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 (Strong) requires allele frequency >0.01%. The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies in absence of Fanconi anemia phenotype data. No healthy homozygote or FA phenotype data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires well-established functional studies showing no damaging effect. Functional studies show a damaging effect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in affected family members. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 applies to missense variants outside clinically important domains. C44Y lies within the RING domain (aa 2–101). Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies for observation in trans with a pathogenic variant in a recessive gene or cis with a pathogenic variant. No such co-occurrence data are available. 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 variant. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 requires BayesDel no-AF ≤0.15 and SpliceAI ≤0.1. BayesDel score is unavailable. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies for co-observation with another gene’s pathogenic variant and no specific phenotype. No such data are available. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies to reputable source assertions of benign impact without evidence. No such assertion exists. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to silent or intronic variants with no predicted splicing effect. This is a missense variant. Therefore, BP7 is not applied.