ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.470C>T (p.Pro157Leu) (rs777184451)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165108 SCV000215818 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-14 criteria provided, single submitter clinical testing <span style="font-family:arial,sans-serif">The <span style="font-family:arial,sans-serif">p.P157L variant (also known as c.470C>T), located in coding exon 6 of the <span style="font-family:arial,sans-serif">MUTYH gene, results from a C to T substitution at nucleotide position 470. The proline at codon 157 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in conjunction with a pathogenic <span style="font-family:arial,sans-serif">MUTYH mutation in an individual with an attenuated polyposis phenotype; however, the phase (cis vs trans) of these two alterations was not determined (Aretz S et al. Int. J. <span style="font-family:arial,sans-serif">Cancer 2006 Aug;119(4):807-14; Vogt S et al. <span style="font-family:arial,sans-serif">Gastroenterology 2009 Dec;137(6):1976-85.e1-10). There is another report of this alteration being identified in an Italian individual with polyps at age 45 in conjunction with a different pathogenic MUTYH mutation (Ricci MT et al. J. Hum. Genet. 2017 Feb;62(2):309-315). This alteration has also been identified in our clinical laboratory in conjunction with pathogenic MUTYH mutations in individuals with adenomatous polyps, but the phase of these alterations was not determined (Ambry internal data). In a functional study, the ability of human MUTYH variant proteins to complement a Mut-deficient E. coli strain was measured and this variant demonstrated partially defective function; however, protein expression and subcellular localization were similar to wild type MUTYH (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). <span style="background-color:initial">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 majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000226581 SCV000285951 pathogenic MYH-associated polyposis 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 157 of the MUTYH protein (p.Pro157Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs777184451, ExAC 0.002%). This variant has been observed to be homozygous or in combination with another pathogenic MUTYH variant in individuals affected with MUTYH-related disease (PMID: 19394335, 27829682, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.428C>T (p.Pro143Leu) in the literature. ClinVar contains an entry for this variant (Variation ID: 185653). An experimental study has shown that this missense change partially disrupts protein function (PMID: 25820570). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000165108 SCV000905865 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-21 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355674 SCV001550625 likely pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.