ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.454G>A (p.Val152Met) (rs748417604)

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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 RCV000163977 SCV000214577 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000222401 SCV000279325 uncertain significance not provided 2018-10-26 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.454G>A at the cDNA level, p.Val152Met (V152M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has been observed in at least one individual with a personal and family history of colorectal cancer (Chubb 2015). MLH1 Val152Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. MLH1 Val152Met occurs at a position that is conserved across species and is located within the N-terminal ATPase domain (Anderson 2012). Protein based in silico analyses predict that this variant is probably damaging to protein structure and function while splicing based models predict this variant to either weaken or destroy the natural splice acceptor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether MLH1 Val152Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000540116 SCV000625164 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-07-30 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 152 of the MLH1 protein (p.Val152Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs748417604, ExAC 0.002%). This variant has been observed in an individual with a personal and family history of colorectal cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 184683). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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 RCV000163977 SCV000689887 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-20 criteria provided, single submitter clinical testing

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