ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.230G>C (p.Cys77Ser) (rs63750437)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480847 SCV000571636 likely pathogenic not provided 2017-03-21 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.230G>C at the cDNA level, p.Cys77Ser (C77S) at the protein level, and results in the change of a Cysteine to a Serine (TGT>TCT). Functional interrogation of this variant by MLH1 human-yeast hybrid assay demonstrated a 34-66% loss of MMR function (Ellison 2004). Of note, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies additional variants at this residue, MLH1 Cys77Arg and MLH1 Cys77Tyr, as pathogenic based on observation in families with Lynch syndrome, as well as functional data (Shimodaira 1998, Nystrom-Lahti 2002, Raevaara 2005, Takahashi 2007, Thompson 2013, Thompson 2014). MLH1 Cys77Ser was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Cysteine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Cys77Ser occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MLH1 Cys77Ser to be a likely pathogenic variant.

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