ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1163T>C (p.Leu388Pro) (rs1060501335)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465018 SCV000545761 pathogenic MYH-associated polyposis 2020-02-14 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 388 of the MUTYH protein (p.Leu388Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with adenomatous polyposis (PMID: 16134147, 16941501, 17949294). In two of these individuals, this variant has been observed on the opposite chromosome (in trans) from a pathogenic variant (PMID: 16134147, 16941501). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as c.1121 T>C, p.Leu374Pro, and p.L360P in the literature. Experimental studies have shown that this missense change severely impairs MUTYH DNA glycosylase activity (PMID: 25820570, 23322991, 20848659). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000465018 SCV000697667 likely pathogenic MYH-associated polyposis 2021-07-26 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1163T>C (p.Leu388Pro) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250094 control chromosomes (gnomAD and publications). c.1163T>C has been reported in the literature in compound heterozygous individuals affected with MUTYH-Associated Polyposis (e.g. Aceto_2005, Lejeune_2006). These data indicate that the variant is likely to be associated with disease. Experimental evidence demonstrated the variant severely impacts protein activity (e.g. Goto_2010, Shinmura_2012, Komine_2015). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Health, Inc RCV000771347 SCV000903631 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000771347 SCV001170213 pathogenic Hereditary cancer-predisposing syndrome 2020-04-03 criteria provided, single submitter clinical testing The p.L388P pathogenic mutation (also known as c.1163T>C), located in coding exon 12 of the MUTYH gene, results from a T to C substitution at nucleotide position 1163. The leucine at codon 388 is replaced by proline, an amino acid with similar properties. This alteration has been identified in one individual with approximately 40 colorectal adenomas in conjunction with a pathogenic founder mutation in MUTYH; the authors report this patient had no detectable APC mutation and that family studies confirmed these MUTYH alterations to be in trans, but did not provide further details (Aceto G et al. Hum. Mutat. 2005 Oct; 26(4):394). This alteration has been identified in several other individuals with multiple polyps; however, phase was not determined and specific clinical information including polyp count was not provided (Lejeune S et al. Hum. Mutat. 2006 Oct; 27(10):1064; Olschwang S et al. Genet. Test. 2007; 11(3):315-20). This alteration has also been detected in conjunction with another pathogenic mutation in MUTYH by our laboratory, but phase is unknown (Ambry internal data). Various functional assays designed to measure base excision repair function have found this alteration to result in a severely deficient protein (Goto M et al. Hum. Mutat. 2010 Nov; 31(11):E1861-74; Shinmura K et al. World J. Gastroenterol. 2012 Dec; 18(47):6935-42; Komine K et al. Hum. Mutat. 2015 Jul; 36(7):704-11). Of note, this alteration is also designated as p.L360P and p.L374P in published literature. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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