ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1835T>C (p.Val612Ala)

dbSNP: rs2085310197
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001066264 SCV001231271 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-08 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 612 of the MLH1 protein (p.Val612Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 860023). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function with a negative predictive value of 95%. This variant disrupts the p.Val612 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15849733, 16083711, 21404117, 24362816). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx RCV001772294 SCV002003126 uncertain significance not provided 2020-07-13 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002411593 SCV002716977 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-23 criteria provided, single submitter clinical testing The p.V612A variant (also known as c.1835T>C), located in coding exon 16 of the MLH1 gene, results from a T to C substitution at nucleotide position 1835. The valine at codon 612 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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