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

gnomAD frequency: 0.00004  dbSNP: rs80357328

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081263	SCV000075861	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132467	SCV000187561	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-26	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 (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40). 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, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Counsyl	RCV000083184	SCV000489708	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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	likely benign	not specified	2022-11-24	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 4e-05 in 150946 control chromosomes (gnomAD v3.1.2). 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 (example, Borg_2010). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with one other pathogenic variant have been reported in the BIC database (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. Eight ClinVar submitters have assessed the variant since 2014: five classified the variant as of uncertain significance and three as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000586521	SCV000806918	uncertain significance	not provided	2017-10-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132467	SCV000903173	likely benign	Hereditary cancer-predisposing syndrome	2017-04-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132467	SCV002538128	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132467	SCV003847642	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).
Sharing Clinical Reports Project (SCRP)	RCV000083184	SCV000115258	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-07-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083184	SCV000144447	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1999-04-12	no assertion criteria provided	clinical testing