Submissions for variant NM_007294.4(BRCA1):c.71G>A (p.Cys24Tyr)

dbSNP: rs80357198

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165179	SCV000215891	pathogenic	Hereditary cancer-predisposing syndrome	2024-12-02	criteria provided, single submitter	clinical testing	The p.C24Y pathogenic mutation (also known as c.71G>A and 190G>A), located in coding exon 1 of the BRCA1 gene, results from a G to A substitution at nucleotide position 71. The cysteine at codon 24 is replaced by tyrosine, an amino acid with highly dissimilar properties. In one study, this alteration was seen in 1 of 1,010 Czech high risk breast and/or ovarian cancer patients (Machackova, E et al. BMC Cancer. 2008 May 20;8:140). This variant is non-functional in multiple assays including BARD1 binding, E3 Ubiquitin Ligase activity and a haploid cell survival assay (Findlay GM. Nature. 2018 10;562(7726):217-222; Starita LM et al. Genetics, 2015 Jun;200:413-22). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Internal structural assessment shows that this alteration disrupts one if the Zn-binding sites of the BRCA1 RING domain (Ambry internal data; Brzovic PS et al. Nat. Struct. Biol., 2001 Oct;8:833-7; Meenakumari, B & Rajkumar, T. Journal of the Indian Institute of Science. 2012 92:3). Multiple pathogenic alterations are located at this position highlighting its sensitivity to amino acid substitution (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001378926	SCV000699297	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-06-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.71G>A (p.Cys24Tyr) results in a non-conservative amino acid change located in the zinc finger, RING-type domain (IPR001841) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251050 control chromosomes. c.71G>A has been reported in the literature in individuals undergoing genetic testing for a personal and/or family history of breast and/or ovarian cancer (e.g. Machackova_2008, Nakamura_2013, Kwong_2015, Arai_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Functional studies evaluating an impact on protein function showed a damaging effect of this variant on E3 ubiquitin ligase activity, it ability to bind to the BARD1 RING domain, and on homology directed repair (HDR) activity (e.g. Starita_2015, Findlay_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29176636, 30209399, 26187060, 18489799, 24249303, 25823446). ClinVar contains an entry for this variant (Variation ID: 55678). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378926	SCV001576627	pathogenic	Hereditary breast ovarian cancer syndrome	2024-05-31	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 24 of the BRCA1 protein (p.Cys24Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18489799, 24249303, 29176636). This variant is also known as 190G>A. ClinVar contains an entry for this variant (Variation ID: 55678). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 25823446, 30209399). This variant disrupts the p.Cys24 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21725363, 23161852, 25823446, 30209399). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000111685	SCV005058295	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998176	SCV005626151	pathogenic	not provided	2024-05-14	criteria provided, single submitter	clinical testing	The BRCA1 c.71G>A (p.Cys24Tyr) variant has been reported in the published literature in individuals with breast cancer (PMID: 24249303 (2015)) and breast and/or ovarian cancer (PMID: 18489799 (2008)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). The variant is located in a region that is considered important for protein function and/or structure (PMID: 16403807 (2006), PMID: 20103620 (2010)). Experimental studies demonstrated that this variant was damaging to protein function (PMID: 25823446 (2015), PMID: 30209399 (2018)). 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111685	SCV000144186	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	flagged submission	clinical testing
Brotman Baty Institute, University of Washington	RCV000111685	SCV001243735	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro