ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.371G>A (p.Cys124Tyr) (rs730881736)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160520 SCV000211086 uncertain significance not provided 2018-06-06 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.371G>A at the cDNA level, p.Cys124Tyr (C124Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MLH1 Cys124Tyr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Cys124Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000475201 SCV000543650 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-12 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 124 of the MLH1 protein (p.Cys124Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs730881736, ExAC 0.001%) but has not been reported in the literature in individuals with a MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 182515). 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, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000573907 SCV000673829 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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