ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1172A>G (p.Gln391Arg) (rs587782884)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132521 SCV000187618 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing Insufficient evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759079 SCV000888173 uncertain significance not provided 2018-06-22 criteria provided, single submitter clinical testing
Color RCV000132521 SCV000904058 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000202075 SCV000917664 uncertain significance not specified 2018-11-29 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1172A>G (p.Gln391Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246166 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1172A>G has been reported in the literature in an individual affected with ovarian cancer (Kraus_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000811189 SCV000951443 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 391 of the MLH1 protein (p.Gln391Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs587782884, ExAC 0.001%). This variant has been observed in an individual affected with ovarian cancer (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 143002). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202075 SCV000257047 uncertain significance not specified no assertion criteria provided research

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