Submissions for variant NM_007294.4(BRCA1):c.5153-3T>C

gnomAD frequency: 0.00001  dbSNP: rs375639469

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165729	SCV000216470	likely benign	Hereditary cancer-predisposing syndrome	2020-02-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474546	SCV000549402	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002468933	SCV000699214	uncertain significance	not specified	2024-05-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5153-3T>C 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. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 250880 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5153-3T>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (example, Findlay_2018). The most pronounced variant effect results in a functional classification as "intermediate" in homology directed repair (HDR) capacity. The following publication have been ascertained in the context of this evaluation (PMID: 30209399). ClinVar contains an entry for this variant (Variation ID: 91639). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000588488	SCV000730671	likely benign	not provided	2020-08-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30209399, 31131967)
Color Diagnostics, LLC DBA Color Health	RCV000165729	SCV000912006	likely benign	Hereditary cancer-predisposing syndrome	2022-08-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165729	SCV002537817	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-12	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000077156	SCV000108953	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2009-10-13	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000077156	SCV001243686	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro