ClinVar Genomic variation as it relates to human health

In-frame deletion of 10 amino acids in a non-repeat region predicted to critically alter the protein: disrupts the ATPase domain (Warren et al., 2007, Kansikas et al., 2011); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28765196, 25504618, 29922827, 17531815, 21120944, 34145315)

This variant, c.3744_3773del, results in the deletion of 10 amino acid(s) of the MSH6 protein (p.His1248_Ser1257del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individuals with Lynch syndrome-related cancers and Lynch syndrome (Invitae; External communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218070). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.

The c.3744_3773del30 pathogenic mutation (also known as p.H1248_S1257del) is located in coding exon 8 of the MSH6 gene. This mutation results from an in-frame deletion of 30 nucleotides at positions 3744 to 3773 and causes the removal of 10 well-conserved amino acid residues at codons 1248 to 1257. This mutation has been seen in individuals with Lynch syndrome, including three families meeting Amsterdam criteria with tumor results from one family showing loss of MSH6 protein on immunohistochemistry (Chang K et al. JAMA Oncol, 2018 08;4:1085-1092; Ambry internal data). This mutation was also reported in a woman whose endometrial tumor demonstrated loss of MSH6 on IHC (Dedeurwaerdere F et al. Sci Rep, 2021 06;11:12880). In addition, this mutation segregated with disease in the three families with a combined LOD score of 1.8 (Ambry internal data). Based on internal structural analysis, this alteration results in a distortion of the α-helix of a protein-protein interface of MSH6, significantly altering the surrounding residues (Warren JJ et al. Mol. Cell. 2007 May; 26(4):579-92). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Variant summary: MSH6 c.3744_3773del30 (p.His1248_Ser1257del) results in an in-frame deletion that is predicted to remove 10 amino acids from the encoded protein. The variant allele was found at a frequency of 4e-06 in 251206 control chromosomes. c.3744_3773del30 has been reported in the literature in individuals affected with Lynch Syndrome (Chang_2018). These data do not allow any conclusion about variant significance. Co-occurrences with a pathogenic variant has been reported (APC c.487C>T, p.Gln163X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and indicated that this variant co-segregates with lynch syndrome-related cancers in multiple families. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This variant causes an in-frame deletion of 10 amino acids at exon 8 of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated cancer (PMID: 29710228; ClinVar SCV000580154.5, SCV000624910.8), and in an individual affected with mismatch repair deficient endometrial cancer (PMID: 34145315).This variant has been identified in 1/251206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

This variant causes an in-frame deletion of 10 amino acids at exon 8 of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated cancer (PMID: 29710228; ClinVar SCV000580154.5, SCV000624910.8), and in an individual affected with mismatch repair deficient endometrial cancer (PMID: 34145315).This variant has been identified in 1/251206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.