ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4985T>C (p.Phe1662Ser) (rs28897695)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112441 SCV000244375 benign Breast-ovarian cancer, familial 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 = 0.000161
Ambry Genetics RCV000130003 SCV000184828 benign Hereditary cancer-predisposing syndrome 2016-03-01 criteria provided, single submitter clinical testing
Counsyl RCV000112441 SCV000489327 benign Breast-ovarian cancer, familial 1 2016-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000443012 SCV000526839 likely benign not specified 2018-02-06 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.
Color RCV000130003 SCV000911091 benign Hereditary cancer-predisposing syndrome 2016-02-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000443012 SCV000916779 likely benign not specified 2018-07-11 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4985T>C (p.Phe1662Ser) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant affects the second to last nucleotide of exon 15, however 4/5 computational tools predict no significant impact on normal splicing which has been confirmed by a validated mini-gene assay (Ahlborn_2015). The variant allele was found at a frequency of 1.2e-05 in 244740 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.4985T>C, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (ElSaghir_2015, Park_2017, Ryu_2017, Judkins_2005), without strong evidence for causality. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.5074+1G>A), providing supporting evidence for a benign role. The variant has been reported as benign by several computational methods, including likelihood ratios models which include functional assays (Woods_2016, Millot_2012, Thouvenot_2016). 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/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112441 SCV000145231 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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