ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.453_458dup (p.Met153_Gln154insIleTrp) (rs876660190)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215777 SCV000277400 pathogenic Hereditary cancer-predisposing syndrome 2019-10-24 criteria provided, single submitter clinical testing 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000461918 SCV000545709 pathogenic MYH-associated polyposis 2020-07-19 criteria provided, single submitter clinical testing This sequence change inserts 6 nucleotides in exon 5 of the MUTYH mRNA (c.453_458dupATGGAT). This leads to the insertion of 2 amino acid residues in the MUTYH protein (p.Trp152_Met153insIleTrp) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous or as co-occuring with pathogenic variants in MUTYH in four individuals affected with MUTYH-associated polyposis (PMID: 26446593, 12606733, 16557584). These findings are consistent with autosomal recessive inheritance, and suggest that this variant contributes to disease. This variant is also known as 137insIW, p.137insIleTrp, c.411_416dupATGGAT and 411dupATGGAT in the literature. ClinVar contains an entry for this variant (Variation ID: 233094). Experimental studies have shown that this in-frame insertion results in reduced substrate binding, impaired glycosylase activity and increased sensitivity to DNA damaging agents in mouse cells harboring this variant (PMID: 20418187, 19953527). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000484268 SCV000568583 likely pathogenic not provided 2018-11-12 criteria provided, single submitter clinical testing This in-frame duplication of six nucleotides in MUTYH is denoted c.453_458dupATGGAT at the cDNA level and p.Trp152_Met153insIleTrp (W152_M153insIW) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is CCGG[dupATGGAT]GCAG. This duplication, also defined as MUTYH c.411_416dupATGGAT or 137insIW, results in an in-frame insertion of two amino acids (Isoleucine and Tryptophan). MUTYH Trp152_Met153insIleTrp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This duplication is not located in a known functional domain. MUTYH Trp152_Met153insIleTrp was observed in the homozygous state in an individual described as having attenuated polyposis at age 40 (Aretz 2006). Additionally, this variant has been reported in the compound heterozygous state with a second MUTYH variant in at least two individuals with a phenotype consistent with either classic or attenuated familial adenomatous polyposis (Sieber 2003, Papp 2015). Functional studies have demonstrated that, compared to wild-type, MUTYH Trp152_Met153insIleTrp had weaker localization to the nucleus, reduced DNA glycosylase activity, and higher levels of DNA 8-oxodG accumulation (D?Agostino 2010, Molatore 2010). We consider this duplication to be likely pathogenic.
Color Health, Inc RCV000215777 SCV000685629 pathogenic Hereditary cancer-predisposing syndrome 2020-11-23 criteria provided, single submitter clinical testing 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.
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV000461918 SCV001774803 likely pathogenic MYH-associated polyposis 2021-08-07 no assertion criteria provided clinical testing

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