Submissions for variant NM_007294.4(BRCA1):c.694G>A (p.Asp232Asn)

gnomAD frequency: 0.00011  dbSNP: rs55975699

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085836	SCV000077114	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131176	SCV000186123	likely benign	Hereditary cancer-predisposing syndrome	2020-02-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590689	SCV000296465	benign	not provided	2023-05-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000590689	SCV000566874	uncertain significance	not provided	2023-07-26	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer (Ricks-Santi et al., 2017; McDonald et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate homology-directed repair as well as cisplatin and olaparib sensitivity similar to wildtype (Bouwman et al., 2020); Also known as 813G>A; This variant is associated with the following publications: (PMID: 15235020, 15385441, 16267036, 27882345, 10923033, 27466509, 25348012, 20215511, 9788437, 9926942, 9582019, 31853058, 32377563, 29884841, 28439188, 31911673, 32546644, 36315513)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175356	SCV000699295	likely benign	not specified	2023-11-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.694G>A (p.Asp232Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 247988 control chromosomes, predominantly at a frequency of 0.00045 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. In addition, this variant was found at a frequency of 0.001954 in African American subpopulation in the Flossies database which consists of approximately 7,000 European American and 3,000 African American women, older than age 70 years who never had cancer. c.694G>A has been reported in the literature in individuals undergoing genetic testing of BRCA1/2 genes in patients from hereditary breast/ovarian cancer families and in African American high-risk breast cancer patients without strong evidence of causality (Judkins_2005, Ricks-Santi_2017). These report(s) 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: 16267036, 15385441, 15235020, 28439188). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=7) and benign/likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000131176	SCV000902979	likely benign	Hereditary cancer-predisposing syndrome	2016-04-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000112773	SCV001482789	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2019-07-27	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000590689	SCV001716313	uncertain significance	not provided	2020-03-09	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000112773	SCV002051780	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2021-11-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001175356	SCV002068168	uncertain significance	not specified	2017-12-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131176	SCV002537892	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-11	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131176	SCV003848009	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112773	SCV000145666	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000112773	SCV000207335	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-06	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004758635	SCV000806983	uncertain significance	BRCA1-related disorder	2024-08-04	no assertion criteria provided	clinical testing	The BRCA1 c.694G>A variant is predicted to result in the amino acid substitution p.Asp232Asn. This variant was reported as a variant of uncertain significance in individuals with breast cancer (Table 1, Ricks-Santi et al 2017. PubMed ID: 28439188; Supplementary Table 2, McDonald. 2022. PubMed ID: 36315513). Functional characterization of this variant has shown that it has a neutral effect (Supplementary Table 2, Bouwman et al. 2020. PubMed ID: 32546644). This variant is reported in 0.054% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/55672/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
BRCAlab, Lund University	RCV000112773	SCV004244151	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing