ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5191G>A (p.Glu1731Lys) (rs397507244)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000549475 SCV000636016 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-07-05 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1731 of the BRCA1 protein (p.Glu1731Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 91641). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV001023693 SCV001185606 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-04 criteria provided, single submitter clinical testing Insufficient evidence
Sharing Clinical Reports Project (SCRP) RCV000077158 SCV000108955 uncertain significance Breast-ovarian cancer, familial 1 2011-07-18 no assertion criteria provided clinical testing
Center of Medical Genetics and Primary Health Care RCV001090053 SCV000987235 likely pathogenic Familial cancer of breast 2020-04-08 no assertion criteria provided research ACMG Guidelines 2015 criteria The BRCA1 variant p.Glu1731Lys is in exon 19 in the BRCT domain (S1642-1736V aa). This domain of about 95 amino acids is found in a large variety of proteins involved in DNA repair, recombination and cell cycle control (Bork et al., 1997). It is found in a mutational hotspot including 34 pathogenic missense, nonsense, and frameshift variants (PM1 Pathogenic Moderate). The allele frequency in GnomAD exomes is 0.0000159 which is less the threshold 0.0001for recessive gene BRCA1, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). 8 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationTaster, REVEL and SIFT versus 3 benign predictions from DEOGEN2, MutationAssessor and PrimateAI support its deleterious effect (PP3 Pathogenic Supporting). In this study this variant was found in a 51-year-old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Likely Pathogenic.
Brotman Baty Institute,University of Washington RCV000077158 SCV001241844 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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