Submissions for variant NM_007294.4(BRCA1):c.81-13C>A

dbSNP: rs56328013

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703434	SCV000209899	likely benign	not provided	2020-10-06	criteria provided, single submitter	clinical testing	Thry JC et al. (2011) European journal of human genetics : EJHG 19 (10):1052-8 (PMID: 21673748); This variant is associated with the following publications: (PMID: 23893897, 21673748, 22505045, 21523855, 26287763, 30209399)
Invitae	RCV001083217	SCV000259494	benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000159855	SCV000602727	likely benign	not specified	2017-02-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580970	SCV000683363	likely benign	Hereditary cancer-predisposing syndrome	2016-10-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000159855	SCV000699307	benign	not specified	2022-03-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.81-13C>A 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. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 3' acceptor site, two predict the variant weakens a 3' acceptor site. However, two functional studies showed that this variant does not affect splicing (Thery 2011, Houdayer 2012). The variant allele was found at a frequency of 6.1e-05 in 246308 control chromosomes, predominantly within the African subpopulation at a frequency of 0.00069 in the gnomAD database. This frequency is close to the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.001). In addition, the variant was reported in 4 / 2559 African American women (i.e. with a frequency of 0.001563), who were older than 70 years of age, and never had cancer (in the FLOSSIES database). These data suggest that the variant is likely a benign polymorphism found primarily in the populations of African origin. c.81-13C>A has been reported in the literature in an African American individual affected with breast cancer (example, Pal 2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Several co-occurrences with other (potentially) pathogenic variants have been observed (in the BIC database: BRCA1 c.5165C>T, p.Ser1722Phe; at our laboratory: BRCA2 c.3264dupT, p.Gln1089fsX10, BRCA1 c.2624delC, p.Pro875fs), providing supporting evidence for a benign role. At least one publication reported experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on Homology Directed Repair (HDR) activity (Findlay 2018). Four 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 (1x) or likely benign (3x). Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000580970	SCV002537910	likely benign	Hereditary cancer-predisposing syndrome	2021-03-29	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000031281	SCV000053886	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2008-03-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031281	SCV000144220	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031281	SCV001237810	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro