ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.523A>G (p.Lys175Glu)

dbSNP: rs1567806027
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000697900 SCV000826533 uncertain significance Hereditary breast ovarian cancer syndrome 2023-11-17 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 175 of the BRCA1 protein (p.Lys175Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 575630). 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%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192477 SCV001360619 uncertain significance not specified 2019-04-02 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.523A>G (p.Lys175Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 277216 control chromosomes (gnomAD database). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.523A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
MGZ Medical Genetics Center RCV003607342 SCV002581022 likely benign Familial cancer of breast 2024-02-09 criteria provided, single submitter clinical testing ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP
Ambry Genetics RCV002334336 SCV002645363 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-01 criteria provided, single submitter clinical testing The p.K175E variant (also known as c.523A>G), located in coding exon 6 of the BRCA1 gene, results from an A to G substitution at nucleotide position 523. The lysine at codon 175 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV002334336 SCV004361109 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-06 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamic acid at codon 175 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has not been identified 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.

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