ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2089C>G (p.Leu697Val) (rs876661149)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214352 SCV000279669 uncertain significance not provided 2015-12-06 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2089C>G at the cDNA level, p.Leu697Val (L697V) at the protein level, and results in the change of a Leucine to a Valine (CTC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Leu697Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. MLH1 Leu697Val occurs at a position that is conserved through mammals and is located in the Pms1p-interactive domain and region of interaction with PMS2, MLH3, and PMS1 (Pang 1997, Raevaara 2005). 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 Leu697Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000579797 SCV000684798 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-18 criteria provided, single submitter clinical testing
Invitae RCV000800252 SCV000939953 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-17 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 697 of the MLH1 protein (p.Leu697Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. 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: 234666). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000579797 SCV001175089 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-08 criteria provided, single submitter clinical testing Insufficient evidence

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