ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1489C>T (p.Arg497Trp) (rs200830026)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132432 SCV000187526 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000168002 SCV000218653 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 497 of the MLH1 protein (p.Arg497Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs200830026, ExAC 0.02%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 142946). 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, 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.
GeneDx RCV000588886 SCV000569883 uncertain significance not provided 2017-01-11 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1489C>T at the cDNA level, p.Arg497Trp (R497W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Arg497Trp was not observed at a significant allele frequency in 1000 Genomes. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Arg497Trp occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the PMS2/PMS1 interaction domain and region of interaction with EXO1 (Pang 1997, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Arg497Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000132432 SCV000684750 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588886 SCV000696114 uncertain significance not provided 2016-11-01 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1489C>T (p.Arg497Trp) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&Go not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/121412 (1/40469), which does not exceed the estimated maximal expected allele frequency for a pathogenic MLH1 variant of 1/1407. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, however, multiple clinical diagnostic laboratories cite the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."

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