ClinVar Genomic variation as it relates to human health

This variant is denoted MSH6 c.3749_3750insACCA(aka c.3746_3749dupACCA) at the cDNA level and p.His1250GlnfsX26 (H1250QfsX26) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is CACT{dupACCA}TTCA. The duplication causes a frameshift, which changes a Histidine to a Glutamine at codon 1250 in exon 8, and creates a premature stop codon at position 26 of the new reading frame. This mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this mutation has not been previously reported to our knowledge, it is considered pathogenic. and is indicative of Lynch syndrome, an autosomal dominant condition that predisposes to colorectal and endometrial cancer as well as other cancers. The predominant MSH6-related cancer risks for individuals who have not been diagnosed with cancer have been estimated as 44% lifetime risk for colorectal cancer for men, 20% lifetime risk for colorectal cancer in women, 44% lifetime risk for endometrial cancer and 1-11% risk for ovarian cancer in women (Baglietto 2010, Kohlmann 2012). MSH6 carriers also have an increased risk for ovarian, stomach, biliary tract, small bowel, urothelium, and brain cancers (Baglietto 2010). A recent prospective study reported an increased risk for breast cancer and pancreatic cancer in individuals with Lynch syndrome (Win 2012). Some individuals with Lynch syndrome have sebaceous neoplasms of the skin (Muir Torre variant) or glioblastomas (Turcot variant). Individuals with Lynch syndrome who have been diagnosed with colon or endometrial cancers have an increased risk for a second primary diagnosis of a Lynch syndrome-associated cancer (Palomaki 2009, Win 2013).Constitutional mismatch repair deficiency (CMMR-D) syndrome is a rare autosomal recessive condition caused by two mutations (one affecting each allele) of the mismatch repair genes including MSH6 This condition is characterized by an increased risk for certain cancers in children including hematologic malignancies, brain tumors, and colon cancer as well as multiple adenomatous polyps and café-au-lait macules (Durno 2010, Wimmer 2010). If a MSH6 mutation carrier's partner is also heterozygous for a MSH6 mutation, the risk to have a child with CMMR-D is 25% with each pregnancy. The variant is found in COLYNCH-HEREDIC panel(s).

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 127590). This premature translational stop signal has been observed in individual(s) with endometrial cancer (PMID: 26681312). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His1250Glnfs*26) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816).

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

The c.3746_3749dupACCA pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a duplication of ACCA at nucleotide position 3746, causing a translational frameshift with a predicted alternate stop codon (p.H1250Qfs*26). This mutation has been reported in several Lynch syndrome individuals (Maxwell KN et al. Am J Hum Genet, 2016 May;98:801-817; Susswein LR et al. Genet Med, 2016 08;18:823-32; Roberts ME et al. Genet Med, 2018 10;20:1167-1174). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.