ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.389-1G>A (rs372267274)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166470 SCV000217267 pathogenic Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing The c.389-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 5 in the MUTYH gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native acceptor splice site; however, direct evidence is insufficient at this time (Ambry internal data). This mutation has been identified in conjunction with a MUTYH founder mutation in two individuals with polyposis (Sampson JR et al. Lancet 2003 Jul;362:39-41; Vogt S et al. Gastroenterology 2009 Dec;137(6):1976-85.e1-10). Of note, this mutation is also designated as 347-1G>A in published literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000469315 SCV000545764 pathogenic MYH-associated polyposis 2020-10-14 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 of the MUTYH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with colorectal cancer and multiple polyposis (PMID: 12853198, 19732775, 24470512, 19032956). This variant is also known as c.347-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 186819). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MUTYH are known to be pathogenic (PMID: 20663686, 18534194). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000166470 SCV000685622 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-04 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358068 SCV001553716 pathogenic not provided no assertion criteria provided clinical testing The MUTYH, c.389-1G>A variant was identified in 8 of 3318 proband chromosomes (frequency: 0.002) from individuals or families with colorectal adenomatous polyposis in the German, UK, Dutch and Spanish populations (Guarinos 2014, Nielsen 2009, Vogt 2009, Sampson 2003, Filipe 2009). The variant was identified in dbSNP (ID: rs372267274) as “With Pathogenic allele.” In the NHLBI Exome Sequencing Project, the variant was identified in 1 of 8600 European Americans and was not identified in African Americans. The variant was listed in the ClinVar database as Pathogenic by Ambry Genetics and was reported 4x in InSiGHT Colon Cancer Gene Variant Database (LOVD). Additionally, the variant was found to occur in biallelic mode with the pathogenic variant c.536A>G in a patient with 14 polyps but no colorectal cancer (Sampson 2003). The variant was identified in 2 patients with attenuated FAP in trans with the pathogenic variant c.1187G>A (Filipe 2009). The c.389-1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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