ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4676-7C>T (rs80358005)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000031187 SCV000154009 likely benign Breast-ovarian cancer, familial 1 2014-01-02 criteria provided, single submitter literature only
GeneDx RCV000159889 SCV000209973 benign not specified 2014-08-20 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 RCV000456921 SCV000560246 likely benign not provided 2019-02-04 criteria provided, single submitter clinical testing
Color RCV000581092 SCV000683203 benign Hereditary cancer-predisposing syndrome 2016-12-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000159889 SCV000699163 likely benign not specified 2019-02-08 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4676-7C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. This prediction was confirmed by a study that demonstrated by RNA analysis from patient lymphocytes that the variant does not affect splicing (Byers 2016). The variant allele was found at a frequency of 3.6e-05 in 249608 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4676-7C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins 2005, Byers 2016), however without strong evidence for causality. Co-occurrence with another pathogenic variant has also been reported (ATM c.7271T>G, p.Val2424Gly; Byers 2016), providing supporting evidence for a benign role. In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be likely neutral (Easton 2007 and Lindor 2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as benign (1x) / likely benign (1x). Our laboratory classified this variant as a "VUS-possibly normal" in October-2016, however, no new evidence supporting pathogenicity have been reported since our original classification. Therefore, the overall evidence seems to be shifting from uncertain significance to likely benign consistent with all the evidence outlined above. Based on this, until more clinical and functional data become available, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000031187 SCV000053787 likely benign Breast-ovarian cancer, familial 1 2012-03-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031187 SCV000145155 uncertain significance Breast-ovarian cancer, familial 1 2000-06-12 no assertion criteria provided clinical testing

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