ClinVar Miner

Submissions for variant NM_007300.4(BRCA1):c.5018T>C (p.Met1673Thr) (rs80356968)

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Total submissions: 11
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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) RCV000031196 SCV000244373 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 = 0.00011
Invitae RCV000195346 SCV000076721 benign not provided 2019-03-04 criteria provided, single submitter clinical testing
GeneDx RCV000048708 SCV000209981 likely benign not specified 2017-07-26 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.
Ambry Genetics RCV000162990 SCV000213478 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
Counsyl RCV000031196 SCV000220544 likely benign Breast-ovarian cancer, familial 1 2014-07-23 criteria provided, single submitter literature only
Color RCV000162990 SCV000683230 likely benign Hereditary cancer-predisposing syndrome 2017-01-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048708 SCV000918687 likely benign not specified 2018-03-13 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4955T>C (p.Met1652Thr) results in a non-conservative amino acid change located to the first BRCT domain that mediates interactions with phosphorylated partner proteins and also functions as a transcriptional activation domain (IPR001357). Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational studies predicted a neutral outcome for the variant (Pruss 2014, Carvalho 2014, Woods 2016), though one study predicted the variant to be deleterious (Karchin 2007). A study based on comparative evolutionary methods predicted a deleterious outcome for this variant (p.Met1652Thr) and another variant affecting this amino acid position (p.Met1652Ile) (Pavlicek 2004), however p.Met1652Ile (c.4956G>A) was classified as benign by our laboratory, indicating that missense changes might tolerated at this position. In an in vitro functional study the variant was reported to have no functional effect on transcriptional activation, phosphopeptide binding and limited proteolysis (that was used to assess the protein folding stability) (Lee 2010), however another study assessing proliferation rate of yeast cell transformants indicated a possible functional defect (Coyne 2004), though this later assay does not provide a direct evidence on protein function. Indeed, a later in vitro study found that this variant (Met1652Thr) cannot be correctly classified by these type of yeast assays (Thouvenot 2016). The variant allele was found at a frequency of 2.2e-05 in 276706 control chromosomes (in gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (2.2e-05 vs 0.001), allowing no conclusion about variant significance. The c.4955T>C variant has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for pathogenicity (Huusko 1998, Meindl 2002, Solano 2013). Thus, these reports do not provide unequivocal conclusions about an association of the variant with Hereditary Breast and Ovarian Cancer. 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, and co-segregation with disease in pedigrees predicted this variant to be neutral (Easton 2007 and Lindor 2012). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as benign/likely benign. Additionally, an internal sample the variant was found in co-occurrence with a pathogenic BRCA2 mutation (c.1813dupA), suggesting the variant of interest was not the cause for disease in this patient. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000031196 SCV001140500 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031196 SCV000053796 benign Breast-ovarian cancer, familial 1 2010-06-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031196 SCV000145221 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
True Health Diagnostics RCV000162990 SCV000787907 likely benign Hereditary cancer-predisposing syndrome 2017-08-28 no assertion criteria provided clinical testing

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