ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1998_1999del (p.Asp667fs) (rs1064794028)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481527 SCV000567626 pathogenic not provided 2015-08-14 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.189A>T at the cDNA level, p.Leu63Phe (L63F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTA>TTT). Using alternate nomenclature, this variant would be defined as BRCA1 308A>T. This variant has been observed in at least one individual with breast and/or ovarian cancer and a child with B-cell acute lymphoblastic leukemia (Brzovic 2001, Zhang 2015). Additionally, BRCA1 Leu63Phe has been shown to disrupt ubiquitin ligase activity of the BRCA1/BARD1 heterodimer and to impair the ability of BRCA1 to repress ER-alpha activity compared to the wild-type controls (Brzovic 2003, Ma 2005, Morris 2006). BRCA1 Leu63Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RING finger and ubiquitination site within the RING domain and interacts with multiple proteins (Wu 1996, Narod 2004, Borg 2010, Harte 2010, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Leu63Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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