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
Ambry Genetics RCV000219992 SCV000275612 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000083120 SCV000147197 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000219992 SCV000683731 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Counsyl RCV000083120 SCV000487956 uncertain significance Breast-ovarian cancer, familial 2 2015-12-18 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000417374 SCV000916829 uncertain significance not specified 2018-01-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.575T>C (p.Met192Thr) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. In a splicing minigene reporter assay the variant was shown not to affect splicing (Di Giacomo 2013). This variant is absent in ~215414 control chromosomes (in gnomAD). This variant was found in patients with pancreatic cancer or early onset breast cancer, but without co-segregation evidence (Murphy 2002, Haffty 2009). In addition, the variant was reported in the LOVD3 database in 2 individuals in co-occurrence with a pathogenic variant in BRCA1 and BRCA2 respectively, which suggests that the variant of interest was not the primary cause of disease. Though multiple clinical diagnostic laboratories classified this variant as uncertain significance, taken together all the available evidence, this variant is classified as VUS-possibly benign, until additional evidence becomes available.
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000417374 SCV000600664 uncertain significance not specified 2016-12-05 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083120 SCV000115194 likely benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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