Submissions for variant NM_007294.4(BRCA1):c.5153-6C>A

gnomAD frequency: 0.00002  dbSNP: rs80358129

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083062	SCV000244389	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000901
GeneDx	RCV000159891	SCV000209986	benign	not specified	2014-09-09	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085661	SCV000253510	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579994	SCV000683264	benign	Hereditary cancer-predisposing syndrome	2016-09-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000159891	SCV000699215	likely benign	not specified	2025-02-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5153-6C>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3' acceptor site. One predict the variant no significant impact on splicing. Two experimental studies showed no impact on splicing (Wappenschmidt_2012, Houdayer_2012). The variant allele was found at a frequency of 2e-05 in 250770 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.5153-6C>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one functional study reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. The following publications have been ascertained in the context of this evaluation (PMID: (30209399, 22505045, 16267036, 23239986). ClinVar contains an entry for this variant (Variation ID: 96941). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590543	SCV000888937	likely benign	not provided	2022-10-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590543	SCV003799421	benign	not provided	2022-03-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000083062	SCV004823314	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-27	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083062	SCV000115136	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2009-01-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083062	SCV000145358	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000083062	SCV001241799	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590543	SCV001956793	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000159891	SCV001971708	benign	not specified		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001085661	SCV002506601	likely benign	Hereditary breast ovarian cancer syndrome	2022-05-04	no assertion criteria provided	clinical testing