ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.694G>A (p.Asp232Asn) (rs55975699)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001085836 SCV000077114 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-24 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 Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590689 SCV000296465 likely benign not provided 2019-11-18 criteria provided, single submitter clinical testing
GeneDx RCV000590689 SCV000566874 uncertain significance not provided 2018-02-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.694G>A at the cDNA level, p.Asp232Asn (D232N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). Using alternate nomenclature, this variant would be defined as BRCA1 813G>A. This variant was observed in at least one individual with a personal history of breast cancer (Ricks-Santi 2017). BRCA1 Asp232Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in a region known to interact with multiple proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Asp232Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175356 SCV000699295 likely benign not specified 2021-05-03 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the emerging majority peer consensus and the evidence outlined above, the variant was re-classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000590689 SCV000806983 uncertain significance not provided 2017-07-20 criteria provided, single submitter clinical testing
Color Health, Inc 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 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
Breast Cancer Information Core (BIC) (BRCA1) RCV000112773 SCV000145666 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000112773 SCV000207335 uncertain significance Breast-ovarian cancer, familial 1 2014-11-06 no assertion criteria provided clinical testing

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