Submissions for variant NM_007294.4(BRCA1):c.5075-9A>T

gnomAD frequency: 0.00001  dbSNP: rs80358059

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000112490	SCV000220675	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-09-07	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200150	SCV000252819	benign	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001284298	SCV000518084	likely benign	not provided	2020-11-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21990134, 29750258, 16267036, 22505045, 26913838, 17924331, 30209399)
Color Diagnostics, LLC DBA Color Health	RCV000582773	SCV000688536	benign	Hereditary cancer-predisposing syndrome	2017-09-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000426508	SCV001338187	benign	not specified	2020-02-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5075-9A>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 8e-06 in 250922 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5075-9A>T has been reported in the literature in studies of individuals affected with Hereditary Breast and Ovarian Cancer, in studies evaluating multifactorial and posterior probability models to assess variant pathogenicity, in splicing studies using PAX gene collection systems and as a training set for evaluating a new prediction protocol aimed at spliceogenic variants (example, Judkins_2005, Easton_2007, Lindor_2012, Houdayer_2012, Leman_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant has been reported in the BIC database (BRCA1 c.1999C>T, p.Gln667*), providing additional supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on splicing. These results showed no damaging effect of this variant on splicing (Houdayer_2012)(class 1S). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=2)/likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284298	SCV001470008	likely benign	not provided	2019-12-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112490	SCV004831308	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-11	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112490	SCV000145301	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112490	SCV001237552	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
PreventionGenetics, part of Exact Sciences	RCV004554704	SCV004799926	likely benign	BRCA1-related disorder	2022-08-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).