ClinVar Genomic variation as it relates to human health

In-frame insertion of two amino acids in a non-repeat region; Published functional studies demonstrate weaker localization to the nucleus, reduced DNA glycosylase activity, and higher levels of DNA 8-oxodG accumulation compared to wild type (D'Agostino et al., 2010; Molatore et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.411_416dupATGGAT or 137insIW; This variant is associated with the following publications: (PMID: 19953527, 16287072, 14633673, 12606733, 17161978, 16557584, 26446593, 19725997, 20418187)

This variant, c.453_458dup, results in the insertion of 2 amino acid(s) of the MUTYH protein (p.Trp152_Met153insIleTrp), 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 MUTYH-associated polyposis (PMID: 12606733, 16557584, 26446593). This variant is also known as 137insIW, p.137insIleTrp, c.411_416dupATGGAT and 411dupATGGAT. ClinVar contains an entry for this variant (Variation ID: 233094). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MUTYH function (PMID: 19953527, 20418187). For these reasons, this variant has been classified as Pathogenic.

The c.453_458dupATGGAT variant (also known as p.W152_M153insIW), located in coding exon 5 of the MUTYH gene, results from an in-frame duplication of 6 nucleotides at positions 453 to 458. This results in the insertion of an extra isoleucine and tryptophan residue between codons 152 and 153. This alteration has been detected in trans with a pathogenic MUTYH mutation in a 38-year-old male diagnosed with polyposis, colorectal cancer, and duodenal adenomas, as well as in the homozygous state in a 40-year-old male diagnosed with attenuated polyposis (Sieber OM et al. N Engl J Med. 2003 Feb 27;348(9):791-9; Russell AM et al. Int J Cancer. 2006 Apr 15;118(8):1937-40; Aretz S et al. Int J Cancer. 2006 Aug 15;119(4):807-14). This alteration has also been identified in conjunction with a pathogenic MUTYH mutation in an individual with adenomatous polyposis; however, the phase (whether in cis or trans) was not determined (Ambry internal data). Binding affinity and glycosylase activity assays showed this alteration caused a reduction in activity (Molatore S et al. Hum Mutat. 2010 Feb;31(2):159-66; D'Agostino VG et al. DNA Repair (Amst). 2010 Jun 4;9(6):700-7). Of note, this alteration is designated as 137insIW in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

ACMG criteria used to clasify this variant: PS3_MOD, PS4_MOD, PM4, PM2_SUP

This variant causes a duplication of 6 nucleotides in exon 5 of the MUTYH gene, resulting in in-frame insertion of isoleucine and tryptophan between codons 152 and 153 in the MUTYH protein. This variant is also known as 137insIW, p.137insIleTrp, p.W138_M139insIW, c.411_416dupATGGAT and 411dupATGGAT. Functional studies have shown that this in-frame insertion results in reduced substrate binding and impaired glycosylase activity (PMID: 19953527, 20418187). This variant has been reported in homozygosity or in compound heterozygosity in multiple individuals affected with MUTYH-associated polyposis (PMID: 12606733, 16287072, 16557584, 26446593). This variant has been identified in 1/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.