ClinVar Miner

Submissions for variant NM_012222.2(MUTYH):c.875C>T (p.Pro292Leu) (rs374950566)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164625 SCV000215289 pathogenic Hereditary cancer-predisposing syndrome 2019-03-31 criteria provided, single submitter clinical testing The p.P295L pathogenic mutation (also known as c.884C>T), located in coding exon 10 of the MUTYH gene, results from a C to T substitution at nucleotide position 884. The proline at codon 295 is replaced by leucine, an amino acid with similar properties. This mutation has been described in multiple patients with adenomatous polyposis who were homozygous for this mutation or compound heterozygous for this and another pathogenic MUTYH alteration (Lejeune S et al. Hum. Mutat., 2006 Oct;27:1064; Vogt S et al. Gastroenterology, 2009 Dec;137:1976-85.e1-10; Jones N et al. Gastroenterology, 2009 Aug;137:489-94, 494.e1; quiz 725-6; Morak M et al. Clin. Genet., 2010 Oct;78:353-63; Croitoru ME et al. J Surg Oncol, 2007 May;95:499-506; Yanus GA et al. Clin. Genet., 2018 May;93:1015-1021). In vitro functional studies demonstrate DNA binding activity and base excision repair activity are severely defective (Ali M et al. Gastroenterology 2008 Aug; 135(2):499-507; Komine K et al. Hum. Mutat., 2015 Jul;36:704-11). Of note, this alteration is also described as p.P281L (c.842C>T) in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation.
GeneDx RCV000235921 SCV000293494 pathogenic not provided 2016-02-22 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.884C>T at the cDNA level, p.Pro295Leu (P295L) at the protein level, and results in the change of a Proline to a Leucine (CCA>CTA). This variant was observed in both the homozygous and compound heterozygous state in individuals affected with MUTYH Associated Polyposis (Jones 2009, Nielsen 20009, Vogt 2009, Morak 2010). In addition, this variant showed defective DNA binding capability, compromised base excision activity and near absent glycosylase activity (Ali 2008, Brinkmeyer 2015, Komine 2015), MUTYH Pro295Leu was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. MUTYH Pro295Leu occurs at a position that is conserved across species and is located in the within FeS cluster (Ruggieri 2013). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000456980 SCV000545714 likely pathogenic MYH-associated polyposis 2020-03-18 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 295 of the MUTYH protein (p.Pro295Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs374950566, ExAC 0.002%). This variant has been reported in several individuals affected with polyposis and/or colorectal cancer (PMID: 19732775, 17219385, 20618354, 19394335, 19032956, 16557584), and in the Leiden Open-source Variation Database (PMID: 20725929). This variant co-occurs with different pathogenic alterations in individuals with multiple adenomatous polyps (PMID: 17219385, 19732775, 16941501), and has been reported as homozygous in an affected individual (PMID: 20725929). This variant is also known as c.842C>T (P281L) in the literature. ClinVar contains an entry for this variant (Variation ID: 185242). Experimental studies have shown that this missense change causes defective DNA binding and reduced glycosylase activity in vitro (PMID: 25820570, 26377631, 18534194). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Health, Inc RCV000164625 SCV000685679 pathogenic Hereditary cancer-predisposing syndrome 2020-08-18 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 295 in the FeS cluster domain of the MUTYH protein. 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 have shown that this variant causes deficient mismatch repair and DNA-binding (PMID: 18534194, 26377631). To our knowledge, this variant has been reported in individuals affected with hereditary cancer in the literature MUTYH-associated polyposis (PMID: 116941501, 16557584, 16941501, 17219385, 19032956, 20618354, 29406563). This variant has been identified in 3/251116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Counsyl RCV000456980 SCV000796726 likely pathogenic MYH-associated polyposis 2017-12-22 criteria provided, single submitter clinical testing
GeneKor MSA RCV000164625 SCV000821747 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This missense mutation results in the substitution of amino acid Proline with Leucine at codon 295 of the MUTYH protein. The proline residue is highly conserved and there is physiochemical difference between proline and Leucine (Grantham Score 98). This variant is present at low frequency in population databases (rs374950566, ExAC <0.01%). Additionally, it has been reported in the literature in individuals affected with polyposis and/or colorectal cancer (PMID: 19732775, PMID: 19394335, PMID: 19032956, PMID: 17219385, PMID: 16557584). Experimental studies have confirmed the disrupting effect of this variant in the protein function (PMID: 25820570, PMID: 26377631). The mutation database ClinVar contains entries for this variant (Variation ID: 185242).
CeGaT Praxis fuer Humangenetik Tuebingen RCV000235921 SCV001248081 pathogenic not provided 2018-04-01 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000235921 SCV001449728 likely pathogenic not provided 2019-02-11 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000235921 SCV001762178 pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353603 SCV000592700 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Pro295Leu variant has been reported in 5 probands with multiple adenoma polyposis (MAP) (Lejeune 2006, Jones 2009). All of these probands were homozygous or compound heterozygous. The variant has also been found in a homozygous state in an individual with MAP (Jones 2009). The MUTYH p.Pro295Leu variant was identified in 8 of 1126 proband chromosomes (frequency: 0.007 from individuals or families with multiple adenoma polyposis (MAP) and was not identified in 100 control chromosomes from healthy individuals (Aretz 2006, Croitoru 2007, Lejeune 2006, Vogt 2009); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also identified in HGMD, “InSiGHT Colon Cancer Database” and UMD (4X as a causal variant). The variant was identified by the Exome Variant Server project in 1 of 4405 African American alleles (frequency: 0.0002), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Pro295 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) suggest that the p.Pro295Leu variant may impact the protein. Lejeune (2006) notes that this variant is located in an important functional domain involved in substrate binding and catalysis, and an in vitro functional study demonstrated that the p.Pro295Leu variant was severely defective in both glycosylase and DNA binding (Ali 2008). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001554252 SCV001774841 pathogenic Breast carcinoma 2021-08-08 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000235921 SCV001809199 pathogenic not provided no assertion criteria provided clinical testing

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