ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2071A>G (p.Ile691Val) (rs201748079)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160543 SCV000211120 uncertain significance not provided 2014-06-13 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2071A>G at the cDNA level, p.Ile691Val (I691V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ile691Val was not observed at a significant allele frequency in 1000 Genomes. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ile691Val occurs at a position that is poorly conserved across species and is located in the domain that interacts with PMS2, PMS1, and MLH3 (Raevaara 2005). In addition, in silico analyses predict that this variant is unlikely to alter protein structure or function. Splicing models predict that this variant may result in a new cryptic splice donor site upstream of the natural splice donor site. Based on currently available information, it is unclear whether MLH1 Ile691Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000776447 SCV000911979 likely benign Hereditary cancer-predisposing syndrome 2017-01-03 criteria provided, single submitter clinical testing
Invitae RCV001211711 SCV001383264 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-05-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 691 of the MLH1 protein (p.Ile691Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs201748079, ExAC 0.01%). This variant has not been reported in the literature in individuals with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 182530). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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