ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.786C>G (p.Ile262Met) (rs748553134)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167152 SCV000217982 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000205244 SCV000261355 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 262 of the MLH1 protein (p.Ile262Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs748553134, ExAC 0.002%) but has not been reported in the literature in individuals with a MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 187425). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000479410 SCV000569904 uncertain significance not provided 2017-02-13 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.786C>G at the cDNA level, p.Ile262Met (I262M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATC>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ile262Met 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 Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ile262Met occurs at a position that is conserved across species and is not located in a known functional domain (Raevaara 2005, UniProt). 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 Ile262Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000167152 SCV000684866 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing

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