ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.884C>T (p.Pro295Leu) (rs374950566)

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Total submissions: 7
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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 2017-07-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Deficient protein function by in vitro/ex vivo assay,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
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 2018-12-17 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000456980 SCV000592700 pathogenic MYH-associated polyposis 2014-08-29 criteria provided, single submitter clinical testing
Color RCV000164625 SCV000685679 pathogenic Hereditary cancer-predisposing syndrome 2017-03-06 criteria provided, single submitter clinical testing
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 2018-08-01 criteria provided, single submitter clinical testing

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