ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.290A>G (p.Tyr97Cys) (rs773647920)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163749 SCV000214326 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-12 criteria provided, single submitter clinical testing Insufficient or Conflicting Evidence
Invitae RCV001079692 SCV000219170 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000411697 SCV000487805 uncertain significance Lynch syndrome II 2015-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000486686 SCV000567410 uncertain significance not provided 2017-11-06 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.290A>G at the cDNA level, p.Tyr97Cys (Y97C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has been identified in at least one individual with colon cancer whose tumor showed microsatellite instability (MSI-H) but intact mismatch repair protein expression by immunohistochemistry (Bartley 2012). MLH1 Tyr97Cys was observed at an allele frequency of 0.20% (62/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Tyr97Cys occurs at a position that is conserved across species and is located in the ATP-binding and hydrolysis motif within the ATPase domain (Raevaara 2005, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Tyr97Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000163749 SCV000684812 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-18 criteria provided, single submitter clinical testing

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