ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.81-13C>A (rs56328013)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159855 SCV000209899 likely benign not specified 2017-12-11 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.
Invitae RCV001083217 SCV000259494 benign Hereditary breast and ovarian cancer syndrome 2020-12-03 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 Health, Inc 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 likely benign not specified 2020-10-08 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 8.5e-05 in 277662 control chromosomes, predominantly within the African subpopulation at a frequency of 0.00094 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 (9.4e-05 vs 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 (Pal 2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other (potentially) pathogenic variants have been reported (in the BIC database: BRCA1 c.5165C>T, p.Ser1722Phe; In an internal sample: BRCA2 c.3264dupT, p.Gln1089fsX10), 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 (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 likely benign.
Sharing Clinical Reports Project (SCRP) RCV000031281 SCV000053886 benign Breast-ovarian cancer, familial 1 2008-03-11 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031281 SCV000144220 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000031281 SCV001237810 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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