ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1451A>G (p.Asp484Gly) (rs876659795)

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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 RCV000213760 SCV000276632 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000522050 SCV000617066 uncertain significance not provided 2018-06-20 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1451A>G at the cDNA level, p.Asp484Gly (D484G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MLH1 Asp484Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). MLH1 Asp484Gly is located in the region of interaction with EXO1 (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MLH1 Asp484Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000560187 SCV000625069 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 484 of the MLH1 protein (p.Asp484Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. 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: 232486). 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: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Color RCV000213760 SCV000689813 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-19 criteria provided, single submitter clinical testing

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