ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.973C>T (p.Arg325Trp) (rs1064793519)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478855 SCV000566314 uncertain significance not provided 2016-04-29 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.973C>T at the cDNA level, p.Arg325Trp (R325W) 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 Arg325Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Arg325Trp occurs at a position that is conserved through mammals and is not located in a known functional domain (Raevaara 2005). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Arg325Trp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568652 SCV000662037 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000568652 SCV000689936 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Invitae RCV000630173 SCV000751129 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-06-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 325 of the MLH1 protein (p.Arg325Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. 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: 418912). 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 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.

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