ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2473G>T (p.Asp825Tyr) (rs80357328)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081263 SCV000075861 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132467 SCV000187561 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-23 criteria provided, single submitter clinical testing ​The p.D825Y variant (also known as c.2473G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2473. The aspartic acid at codon 825 is replaced by tyrosine, an amino acid with highly dissimilar properties. In a population based cohort of 705 contralateral and 1398 unilateral breast cancer cases, this alteration was detected in one contralateral breast cancer case. The authors classified this alteration as being of uncertain significance but noted that the prediction from Align-GVGD was class C0, less likely to interfere with function (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40). This alteration has been evaluated by evolutionary conservation analyses in the literature. Two authors predicted this alteration to be deleterious (Fleming MA et al. Proc. Natl. Acad. Sci. U.S.A. 2003 Feb;100:1151-6; Ramirez CJ et al. Oncogene. 2004 Mar;23:1780-8), while a third author predicted this alteration to be of inconclusive significance (Burk-Herrick A et al. Mamm. Genome. 2006 Mar;17:257-70). Of note, this alteration is also designated as 2592G>T in published literature. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000083184 SCV000489708 uncertain significance Breast-ovarian cancer, familial 1 2016-11-11 criteria provided, single submitter clinical testing
GeneDx RCV000435802 SCV000516568 likely benign not specified 2017-09-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586521 SCV000600288 uncertain significance not provided 2019-03-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000435802 SCV000698958 uncertain significance not specified 2019-04-01 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2473G>T (p.Asp825Tyr) 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 6.5e-05 in 30966 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2473G>T has been reported in the literature in individuals affected with Breast Cancer (Borg_2010). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.2468_2468delG, p.Arg823Lysfs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 (2 likely benign, 4 VUS). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics,PreventionGenetics RCV000586521 SCV000806918 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132467 SCV000903173 likely benign Hereditary cancer-predisposing syndrome 2017-04-07 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083184 SCV000115258 likely benign Breast-ovarian cancer, familial 1 2012-07-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083184 SCV000144447 uncertain significance Breast-ovarian cancer, familial 1 1999-04-12 no assertion criteria provided clinical testing

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