ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1757C>A (p.Ala586Asp) (rs63750587)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524249 SCV000284033 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 586 of the MLH1 protein (p.Ala586Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (rs63750587, ExAC no frequency). This variant has been reported in the literature in a family affected with Lynch syndrome (PMID: 16395668) and has been reported to segregate with disease in multiple individuals from two families affected with Lynch syndrome (Invitae). Immunohistochemical analysis of tumors from these individuals revealed loss of MLH1 and PMS2. ClinVar contains an entry for this variant (Variation ID: 89877). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508407 SCV000601366 uncertain significance not specified 2016-09-07 criteria provided, single submitter clinical testing
Color RCV001175812 SCV001339534 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-10 criteria provided, single submitter clinical testing

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