ClinVar Genomic variation as it relates to human health

Variant summary: MLH1 c.1706C>T (p.Ala569Val) results in a non-conservative amino acid change located in the DNA mismatch repair protein MLH1, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245980 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1706C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 569 of the MLH1 protein (p.Ala569Val). 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: 632895). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 alanine with valine at codon 569 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has reported by an external laboratory in multiple individuals affected with colorectal cancer (ClinVar SCV002715812.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.A569V variant (also known as c.1706C>T), located in coding exon 15 of the MLH1 gene, results from a C to T substitution at nucleotide position 1706. The alanine at codon 569 is replaced by valine, an amino acid with similar properties. This alteration has been identified in an individual whose colorectal tumor displayed loss of both MLH1/PMS2 staining on immunohistochemistry (IHC) and had a family history of Lynch-associated cancers (Ambry internal data). This alteration was also identified in an individual whose colorectal tumor displayed high microsatellite instability (MSI-H) with abnormal MLH1/PMS2 staining on IHC and a somatic likely pathogenic variant in MLH1 was identified, but no MLH1 promoter hypermethylation was detected (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

This missense variant replaces alanine with valine at codon 569 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has reported by an external laboratory in multiple individuals affected with colorectal cancer (ClinVar SCV002715812.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.