ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.53T>C (p.Met18Thr) (rs80356929)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131693 SCV000186729 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Breast Cancer Information Core (BIC) (BRCA1) RCV000031245 SCV000144142 uncertain significance Breast-ovarian cancer, familial 1 1999-03-24 no assertion criteria provided clinical testing
Color RCV000131693 SCV000909428 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-20 criteria provided, single submitter clinical testing
Counsyl RCV000031245 SCV000786080 likely pathogenic Breast-ovarian cancer, familial 1 2018-02-23 criteria provided, single submitter clinical testing
GeneDx RCV000212154 SCV000210063 likely pathogenic not provided 2018-08-18 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.53T>C at the cDNA level, p.Met18Thr (M18T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). Using alternate nomenclature, this variant would be defined as BRCA1 172T>C. BRCA1 Met18Thr has been observed in multiple individuals with breast or ovarian cancer, including male breast cancer (Langston 1996, Greenman1998, Malone 1998, van Orsouw 1999), and was reported to segregate with disease in two kindreds (Mohammadi 2009). This variant was predicted by Lindor et al. (2012) to likely be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. Functional studies have found discordant results with respect to ubiquitin ligase activity and BARD1 binding, but have revealed impaired homology-directed repair activity, increased centrosome amplification, and loss of ability to rescue cell growth (Ruffner 2001, Morris 2004, Morris 2006, Sarkar 2008, Ransburgh 2010, Parvin 2011, Kais 2012, Bouwman 2013, Towler 2013, Starita 2015). BRCA1 Met18Thr was not observed in large population cohorts (Lek 2016). This variant is located in the RING domain and a region that binds BRD7 and BARD1 (Narod 2004, Borg 2010, Harte 2010, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available information, we consider BRCA1 Met18Thr to be a likely pathogenic variant.
Sharing Clinical Reports Project (SCRP) RCV000031245 SCV000053849 likely pathogenic Breast-ovarian cancer, familial 1 2011-04-01 no assertion criteria provided clinical testing

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