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; This variant is associated with the following publications: (PMID: 27601186, 25892863, 27093186, 25010007, 17531815, 21120944, 29212164)

This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.

The frequency of this variant in the general population, 0.00022 (4/18394 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer ((PMID: 25892863 (2015), 29212164 (2017)). The variant has also been reported to occur with an MLH1 truncating variant in a family with colorectal cancer (PMID: 25892863 (2015)). In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

This missense variant replaces threonine with serine at codon 767 of the MSH6 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, who also carried a pathogenic truncation in the MLH1 gene that appeared to be responsible for the disease in the family (PMID: 25892863). This variant has been reported in an individual with significant family history of colorectal cancer that was affected with early onset colorectal cancer demonstrating high microsatellite instability (PMID: 29212164), and in an individual affected with breast cancer (DOI: 10.1101/2021.04.15.21255554v2). This variant has also been identified in 4/251156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2300C>T (p.Thr767Ile), is considered to be disease-causing (ClinVar variation ID: 141058), 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 threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 767 of the MSH6 protein (p.Thr767Ser). This variant is present in population databases (rs587781462, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25892863, 29212164). ClinVar contains an entry for this variant (Variation ID: 419197). 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 MSH6 protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the p.Thr767 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29755653, 31100584). 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 threonine with serine at codon 767 of the MSH6 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, who also carried a pathogenic truncation in the MLH1 gene that appeared to be responsible for the disease in the family (PMID: 25892863). This variant has been reported in an individual with significant family history of colorectal cancer that was affected with early onset colorectal cancer demonstrating high microsatellite instability (PMID: 29212164), and in an individual affected with breast cancer (DOI: 10.1101/2021.04.15.21255554v2). This variant has also been identified in 4/251156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2300C>T (p.Thr767Ile), is considered to be disease-causing (ClinVar variation ID: 141058), 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.T767S variant (also known as c.2300C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2300. The threonine at codon 767 is replaced by serine, an amino acid with similar properties. This variant was identified in a Chinese family with early onset colorectal cancer and segregated with disease in 2/3 affected individuals but also co-occurred with an MLH1 frameshift mutation that was present in all three affected individuals tested (Zhang JX et al. World J. Gastroenterol. 2015 Apr;21:4136-49). This variant was also identified in a Filipino male diagnosed with metachronous colorectal cancers at 41 and 62 years old. While his family history met Amsterdam criteria, his tumor was MSI-H and demonstrated absence of PMS2 expression by IHC (Raskin L et al. Oncotarget 2017 Nov;8:93450-93463). This variant was identified in a cohort of 481 Chinese breast cancer patients with family history of breast/ovarian cancer (Wang J et al. Cancer Med, 2019 05;8:2074-2084). This alteration is also designated as p.Thr767Ser in published literature. 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.