Submissions for variant NM_001048174.2(MUTYH):c.1130C>T (p.Pro377Leu)

gnomAD frequency: 0.00003  dbSNP: rs529008617

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131914	SCV000186969	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-28	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000191934	SCV000285918	pathogenic	Familial adenomatous polyposis 2	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 405 of the MUTYH protein (p.Pro405Leu). This variant is present in population databases (rs529008617, gnomAD 0.01%). This missense change has been observed in individuals with MUTYH-associated polyposis (PMID: 16140997, 16557584, 16616356, 19732775). It is commonly reported in individuals of Dutch ancestry (PMID: 17161978, 20191381). This variant is also known as 1172C>T, P391L, and P377L. ClinVar contains an entry for this variant (Variation ID: 142604). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 19836313, 20848659, 23322991, 25820570). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000413961	SCV000490629	pathogenic	not provided	2023-07-26	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 et al., 2009; Goto et al., 2010; Shinmura et al., 2012; Komine et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23322991, 25820570, 25938944, 23007840, 17674103, 22297469, 19031083, 28152038, 32088803, 32782288, 19836313, 20848659, 19732775, 16140997, 27153395, 28873162, 28790112, 28944238, 27631816, 20191381, 16557584, 16616356, 20618354, 18506705, 17489848, 25937855, 23605219, 31589614, 30787465, 30604180, 34680242, 23108399, 30291343)
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	Familial adenomatous polyposis 2	2017-01-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131914	SCV000685555	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-16	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 Molecular Pathology, 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 Laboratory Services, Illumina	RCV000191934	SCV000915415	pathogenic	Familial adenomatous polyposis 2	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 and Genomics, Karolinska University Hospital	RCV000413961	SCV001449933	pathogenic	not provided	2018-06-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000191934	SCV002017630	pathogenic	Familial adenomatous polyposis 2	2019-02-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000191934	SCV002500746	pathogenic	Familial adenomatous polyposis 2	2022-03-29	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1214C>T (p.Pro405Leu) 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 allele was found at a frequency of 7.2e-05 in 250510 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (7.2e-05 vs 0.0046), allowing no conclusion about variant significance. c.1214C>T has been widely reported in the literature as a Dutch founder mutation in multiple biallelic homozygous and compound heterozygous individuals affected with MUTYH-Associated Polyposis (example, Jones_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Komine_2009). The most pronounced variant effect results in a functionally defective Base Excision Repair (BER) activity in a MutY-Deficient E. coli Complementation Assay. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002492514	SCV002801098	pathogenic	Familial adenomatous polyposis 2; Gastric cancer	2022-05-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000191934	SCV004198838	pathogenic	Familial adenomatous polyposis 2	2024-03-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000191934	SCV004838258	pathogenic	Familial adenomatous polyposis 2	2023-12-13	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000191934	SCV004848061	pathogenic	Familial adenomatous polyposis 2	2019-04-05	criteria provided, single submitter	clinical testing	The p.Pro405Leu variant in MUTYH has been reported in the homozygous or compound heterozygous state in >20 individuals with autosomal recessive MUTYH-related attenuated familial adenomatous polyposis (FAP) or associated cancers (Nielsen 2005, Kanter-Smoler 2006, Aretz 2006, Vogt 2009), and was found to segregate with disease in at least 7 relatives from multiple families (Vogt 2009, Kanter-Smoler 2006). This variant has been suggested to be a Dutch founder mutation (Nielsen 2005). This variant has also been reported in ClinVar (Variation ID: 142604). This variant has been identified in 16/126332 European chromosomes by the Genome Aggregation Database (ExAC, http://exac.broadinstitute.org; dbSNP rs529008617); however, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Pro405Leu variant may impact protein function (Kundu 2009, Goto 2010, Shinmura 2012, Komine 2015). Computational prediction tools and conservation analysis suggest that the p.Pro405Leu variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for MUTYH-related FAP in an autosomal recessive manner based upon segregation studies and functional evidence. ACMG/AMP criteria applied: PM3_VS, PS4, PP1_S, PP3, PS3_P
Pathway Genomics	RCV000144633	SCV000189960	pathogenic	Carcinoma of colon	2014-07-24	no assertion criteria provided	clinical testing
GeneReviews	RCV000191934	SCV000246166	not provided	Familial adenomatous polyposis 2		no assertion provided	literature only	Common in the Dutch population
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000413961	SCV001952002	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000413961	SCV001968492	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000191934	SCV004037518	not provided	Familial adenomatous polyposis 2		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 04-24-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.