ClinVar Genomic variation as it relates to human health

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal cancer (Vodicka et al., 2015); This variant is associated with the following publications: (PMID: 25576899, 22753075, 16083711, 21120944, 25435955)

The frequency of this variant in the general population, 0.000004 (1/251396 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with rectal cancer (PMID: 25435955 (2015)) and thyroid cancer (PMID: 25576899 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

This missense variant replaces isoleucine with methionine at codon 68 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer but without the clinical features of Lynch syndrome (PMID: 25435955). This variant has been identified in 1/251396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.203T>G (p.Ile68Ser) and c.203T>A (p.Ile68Asn), are considered to be disease-causing (ClinVar variation ID: 820585, 90008), suggesting that this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 68 of the MLH1 protein (p.Ile68Met). This variant is present in population databases (rs780141938, gnomAD 0.0009%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 25435955). ClinVar contains an entry for this variant (Variation ID: 486852). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. This variant disrupts the p.Ile68 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10082584, 11304573, 11555625, 12810663, 14961575, 17510385, 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.

This missense variant replaces isoleucine with methionine at codon 68 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer but without the clinical features of Lynch syndrome (PMID: 25435955). This variant has been identified in 1/251396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.203T>G (p.Ile68Ser) and c.203T>A (p.Ile68Asn), are considered to be disease-causing (ClinVar variation ID: 820585, 90008), suggesting that this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.I68M variant (also known as c.204C>G), located in coding exon 2 of the MLH1 gene, results from a C to G substitution at nucleotide position 204. The isoleucine at codon 68 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in both germline and tumor DNA of a 59 year old female with rectal cancer; however, the expression of MLH1 was not altered in the tumor. Authors also report that the amino acid residue 68 is located within the enzymatic core on the MLH1 protein which interacts with ATP; they conclude that a substitution by methionine may decrease MLH1 activity (Vodicka P et al, Oncol Lett 2015 Jan; 9(1):183-186). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.