ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.575T>C (p.Met192Thr) (rs80358805)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000074544 SCV000072759 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-22 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 192 of the BRCA2 protein (p.Met192Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer and pancreatic cancer in the literature (PMID: 19491284, 12097290) and in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 51930). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000417374 SCV000108629 likely benign not specified 2016-10-05 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 RCV000219992 SCV000275612 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000083120 SCV000487956 uncertain significance Breast-ovarian cancer, familial 2 2015-12-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985251 SCV000600664 uncertain significance not provided 2019-08-22 criteria provided, single submitter clinical testing
Color RCV000219992 SCV000683731 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000417374 SCV000916829 uncertain significance not specified 2019-05-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.575T>C (p.Met192Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In a splicing minigene reporter assay, the variant was shown not to affect splicing (Di Giacomo_2013). The variant was absent in 251414 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.575T>C, has been reported in the literature in individuals affected with pancreatic cancer or early onset breast cancer (Murphy_2002, Haffty_2009). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.2722G>T, p.Glu908*; BRCA2 c.7069_7070del, p.Leu2357Valfs*2), providing supporting evidence for a benign role. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS (n=5), likely benign (n=1)). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sharing Clinical Reports Project (SCRP) RCV000083120 SCV000115194 likely benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083120 SCV000147197 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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