ClinVar Miner

Submissions for variant NM_012222.2(MUTYH):c.1205C>T (p.Pro402Leu) (rs529008617)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131914 SCV000186969 pathogenic Hereditary cancer-predisposing syndrome 2019-04-16 criteria provided, single submitter clinical testing The p.P405L pathogenic mutation (also known as c.1214C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1214. The proline at codon 405 is replaced by leucine, an amino acid with similar properties. This mutation was reported in a Dutch cohort of polyposis patients who had previously tested negative for APC mutations; it was seen in 14% of the patients with biallelic MUTYH mutations, including two probands who were homozygous for p.P405L (Nielsen M et al. J. Med. Genet. 2005 Sep;42:e54). In another study examining the extracolonic tumor spectrum in patients with MUTYH-polyposis, authors observed this mutation in 23 out of 376 patients, including four individuals who were homozygous carriers of the p.P405L mutation and 19 compound heterozygotes (Vogt S et al. Gastroenterology 2009 Dec;137:1976-85.e1-10). This alteration has also been identified in a 40-year old male with 100 adenomas in a compound heterozygous state (Morak M et al. Clin. Genet. 2010 Oct;78:353-63). Functional analysis of this alteration has revealed compromised adenine glycosylase activity that was 30-40% of the activity of the wildtype enzyme (Kundu S et al. DNA Repair (Amst.) 2009 Dec;8:1400-10). In addition, several other studies have found this alteration to be functionally defective (Goto M et al. Hum. Mutat. 2010 Nov;31:E1861-74; Shinmura K et al. World J. Gastroenterol. 2012 Dec;18:6935-42; Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). Of note, this alteration is also designated as p.P391L (c.1172C>T) in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000191934 SCV000285918 pathogenic MYH-associated polyposis 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 405 of the MUTYH protein (p.Pro405Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs529008617, ExAC 0.02%). This variant is clearly defined as a MUTYH-associated polyposis causative allele (PMID: 16140997, 16557584, 16616356, 19732775). It is a founder mutation in the Dutch population. This variant is also known as 1172C>T, P391L, and P377L in the literature. ClinVar contains an entry for this variant (Variation ID: 142604). Experimental studies have shown that this missense change severely impacts protein function (PMID: 19836313, 20848659, 25820570, 23322991). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000413961 SCV000490629 pathogenic not provided 2019-07-02 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: variant associated with severely impaired glycosylase activity and severely suppressed oxidative mutagenesis (Kundu 2009, Goto 2010, Shinmura 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30291343, 32088803, 30604180, 28152038, 23605219, 25937855, 17489848, 18506705, 20618354, 16616356, 16557584, 20191381, 27631816, 28944238, 28790112, 28873162, 27153395, 16140997, 19732775, 25820570, 23322991, 20848659, 19836313, 25938944, 23007840, 17674103, 22297469, 19031083)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000413961 SCV000601629 pathogenic not provided 2017-05-12 criteria provided, single submitter clinical testing
Counsyl RCV000191934 SCV000678195 pathogenic MYH-associated polyposis 2017-01-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131914 SCV000685555 pathogenic Hereditary cancer-predisposing syndrome 2020-11-23 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 405 in the nudix hydrolase domain of the MUTYH protein. This variant is also known as c.1172C>T (p.Pro391Leu) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies showed severely reduced glycosylase and bacterial complementation activities (PMID: 19836313, 20848659, 25820570). This variant has been reported in many individuals and families affected with MUTYH-associated polyposis (MAP) (PMID: 16140997, 16557584, 16616356, 17674103, 19732775, 20191381, 20618354, 25938944, 28944238) and is known to be a common disease-causing mutation in the Dutch population (PMID: 16140997, 18172263, 22297469). This variant has been identified in 20/281904 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000722033 SCV000853210 pathogenic B lymphoblastic leukemia lymphoma, no ICD-O subtype 2017-04-04 criteria provided, single submitter clinical testing This is a missense alteration in which a C is replaced by a T at coding nucleotide 1214 and is predicted to change a Proline to a Leucine at amino acid codon 405. Classification criteria: PS3, PM2, PM3, PP3, PP5.
Illumina Clinical Services Laboratory,Illumina RCV000191934 SCV000915415 pathogenic MYH-associated polyposis 2018-12-13 criteria provided, single submitter clinical testing The MUTYH c.1172C>T (p.Pro391Leu) is a missense variant. Across a selection of the available literature, the p.Pro391Leu variant has been found in 19 individuals affected with polyposis, including six in a homozygous state and 13 in a compound heterozygous state (Kanter-Smoler G et al. 2006; Nielsen et al. 2005; Aretz et al. 2006; Middeldorp et al. 2008). The variant was absent from 424 control alleles and is reported at a frequency of 0.000183 in the European (non-Finnish) population of the Exome Aggregation Consortium (Kanter-Smoler G et al. 2006; Aretz et al. 2006). Functional studies demonstrated the variant resulted in severely impaired glycosylase activity (Kundu et al. 2009; Goto et al. 2010) and mutation suppression compared to wild type (Kundu et al. 2009; Shinmura et al. 2012; Komine et al. 2015). The Pro391 residue is conserved across species and is located in a functionally important domain (Kundu et al. 2009). Based on the collective data, the p.Pro391Leu variant is classified as pathogenic for MYH-associated polyposis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000413961 SCV001449933 pathogenic not provided 2018-06-11 criteria provided, single submitter clinical testing
Pathway Genomics RCV000144633 SCV000189960 pathogenic Carcinoma of colon 2014-07-24 no assertion criteria provided clinical testing
GeneReviews RCV000191934 SCV000246166 pathogenic MYH-associated polyposis 2019-10-08 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000144633 SCV000592712 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Pro405Leu (Alias: p.Pro391Leu) variant has been previously reported in the literature in 30/1730 proband chromosomes, of whom 23 were homozygous or compound heterozygous for this variant or a second pathogenic variant, consistent with the autosomal recessive inheritance of the MUTYH-associated polyposis coli. The variant was not observed in 424 controls (Aretz 2006, Bouquen 2007, Goto_2010, Kanter-Smoler 2006, Kundu 2009, Middeldorp 2008, Nielsen 2005, Vogt 2009). The MYH Pro405/391 residue is conserved across mammals, and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the variant may impact the protein. Although this information is not predictive enough to assume pathogenicity, functional studies analyzing the adenine glycosylase activity have shown that the variant showed compromised enzymatic activity that was 30–40% of the wild type enzyme. (Goto 2010, Kundu 2009). In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000413961 SCV001741692 pathogenic not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000413961 SCV001798721 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000413961 SCV001807168 pathogenic not provided no assertion criteria provided clinical testing

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