Submissions for variant NM_007294.4(BRCA1):c.1724A>G (p.Glu575Gly)

gnomAD frequency: 0.00006  dbSNP: rs111539978

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165640	SCV000216376	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-30	criteria provided, single submitter	clinical testing	The p.E575G variant (also known as c.1724A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1724. The glutamic acid at codon 575 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234745	SCV000289750	benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000587405	SCV000293153	uncertain significance	not provided	2023-10-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Identified among individuals with breast cancer (Combrink et al., 2021; Ren et al., 2021); Also known as 1843A>G; This variant is associated with the following publications: (PMID: 32627955, 21702907, 25348012, 16760289, 35464868, 15343273, 34218100, 34196900, 34981296)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587405	SCV000600265	uncertain significance	not provided	2023-02-06	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00025 (4/16242 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 34196900 (2021), 34218100 (2021)). 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.
Color Diagnostics, LLC DBA Color Health	RCV000165640	SCV000682979	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 575 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 been reported in at least two individuals affected with breast cancer (PMID: 34196900, 34218100) and in one individual age 70 years or older without cancer by FLOSSIES (https://whi.color.com/variant/17-41245824-T-C). This variant has been identified in 5/250754 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420708	SCV000698884	likely benign	not specified	2023-12-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1724A>G (p.Glu575Gly) results in a non-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 allele was found at a frequency of 3.1e-05 in 1613682 control chromosomes, predominantly at a frequency of 0.00033 within the African or African-American subpopulation in the gnomAD v4.0.0 database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00033 vs 0.001). However, the variant was also reported from the southern part of Africa with an even higher allele frequency, i.e. 0.029 (6/208 alleles), including 1 homozygote (in the GenomeAsia 100K database). In addition, it was found in 1/ 2559 African American women, who were older than age 70, and have never had cancer (in the FLOSSIES database). These data suggest that the variant could be a benign polymorphism. The variant, c.1724A>G, has been reported in the literature in individuals with a personal of family history of Hereditary Breast And Ovarian Cancer Syndrome (e.g., Combrink_2021, Ren_2021, Hovland_2022, Gifoni_2022), however without strong evidence for causality (e.g., lack of co-segregation data). It has also been reported in the BRCA Share database (formerly UMD-BRCA1) in one proband (without co-occurrence with other deleterious variants in BRCA1/2). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34218100, 35957908, 21702907, 34981296, 25348012, 34196900). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=4) or benign/likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000234745	SCV002025999	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165640	SCV003851081	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000234745	SCV004228085	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995441	SCV004818292	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 575 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 been reported in at least two individuals affected with breast cancer (PMID: 34196900, 34218100) and in one individual age 70 years or older without cancer by FLOSSIES (https://whi.color.com/variant/17-41245824-T-C). This variant has been identified in 5/250754 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.
Mendelics	RCV004700509	SCV005205561	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.