ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1834G>A (p.Val612Ile) (rs587779956)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590125 SCV000149377 uncertain significance not provided 2017-02-23 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1834G>A at the cDNA level, p.Val612Ile (V612I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Val612Ile 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 Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MLH1 Val612Ile occurs at a position that is conserved across species and is located in the region of interaction with PMS2, MLH3, PMS1, and EXO1 (Raevaara 2005, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Val612Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000470919 SCV000543552 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 612 of the MLH1 protein (p.Val612Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 127620). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000568759 SCV000662097 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000568759 SCV000684774 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590125 SCV000696129 uncertain significance not provided 2016-04-18 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1834G>A variant involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a neutral outcome. The variant is absent from the large, broad ExAC control population. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies, however it has been reported as a VUS by one reputable clinical lab. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.

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