ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1481G>A (p.Cys494Tyr) (rs876658198)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222598 SCV000273134 uncertain significance Hereditary cancer-predisposing syndrome 2015-01-09 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000478484 SCV000565962 uncertain significance not provided 2017-02-15 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1481G>A at the cDNA level, p.Cys494Tyr (C494Y) 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 pathogenic or benign. MLH1 Cys494Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Cys494Tyr occurs at a position that is not conserved and is located in the region of interaction with EXO1 (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Cys494Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000810009 SCV000950195 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 494 of the MLH1 protein (p.Cys494Tyr). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 229795). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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