ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.859del (p.Ala287fs) (rs761468459)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV000777643 SCV000913514 pathogenic Hereditary cancer-predisposing syndrome 2020-04-15 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000499908 SCV000967776 likely pathogenic MYH-associated polyposis 2018-09-06 criteria provided, single submitter clinical testing The p.Ala287ProfsX32 variant in MUTYH has been reported in the heterozygous stat e in one individuals with familial adenomatouspolyposis (Aretz 20016). It has al so been identified in 1/30782 of South Asian chromosomes by gnomAD (http://gnoma This variant is predicted to cause a frameshift, which al ters the protein?s amino acid sequence beginning at position 287 and leads to a premature termination codon 32 amino acids downstream. This alteration is then p redicted to lead to a truncated or absent protein. In summary, although addition al studies are required to fully establish its clinical significance, the p.Ala2 87ProfsX32 variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2.
Ambry Genetics RCV000777643 SCV001179223 pathogenic Hereditary cancer-predisposing syndrome 2019-09-18 criteria provided, single submitter clinical testing The c.859delG variant, located in coding exon 10 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 859, causing a translational frameshift with a predicted alternate stop codon (p.A287Pfs*32). This variant (designated as MUTYH c.817delG p.A273PfsX32) has been reported in the heterozygous state in one individual with a clinical diagnosis of familial adenomatouspolyposis. (Aretz S et al. Int. J. Cancer. 2006 Aug;119:807-14).<span style="color:rgb(33, 33, 33); font-family:source sans pro,helvetica neue,helvetica,roboto,arial,sans-serif; font-size:13.6px"> In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000499908 SCV001399526 pathogenic MYH-associated polyposis 2019-08-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala287Profs*32) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs761468459, ExAC 0.006%). This variant has been observed in an individual affected with polyposis (PMID: 16557584). This variant is also known as c.817delG, p.A273PfsX32 in the literature. ClinVar contains an entry for this variant (Variation ID: 433934). Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001310852 SCV001500820 pathogenic not provided 2020-08-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353713 SCV000592699 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Ala287ProfsX32 variant was identified in 1 of 658 proband chromosomes (frequency: 0.002) from individuals or families with MUTYH associated polyposis, and was not identified in 116 control chromosomes from healthy individuals (Aretz 2006). The p.Ala287ProfsX32 variant was also identified in HGMD and the “InSiGHT Colon Cancer Database”. The p.Ala287ProfsX32 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 287 and leads to a premature stop codon 32 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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