ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1187-2A>G (rs587781628)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129730 SCV000184535 pathogenic Hereditary cancer-predisposing syndrome 2017-06-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without splicing assay data in support of pathogenicity,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Pathway Genomics RCV000172819 SCV000223785 pathogenic Carcinoma of colon 2014-10-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000338621 SCV000357894 likely pathogenic MYH-associated polyposis 2016-06-14 criteria provided, single submitter clinical testing The c.1187-2A>G variant, also referred to as c.1145-2A>G and IVS12-2A>G, occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Across three studies, this variant was reported in three colorectal cancer patients, including two patients who carried the variant in a compound heterozygous state with a second known pathogenic variant and in one patient who was heterozygous for the c.1187-2A>G variant (Wang et al. 2004; Eliason et al. 2005; Farrington et al. 2005). The variant was absent from 1845 control individuals but is reported at a frequency of 0.00003 in the European (Non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on only two alleles so it is presumed to be rare. RNA transcript analysis of RNA from one of the compound heterozygous patients revealed only the missense variant transcript and no wild type transcript, indicating that the splice acceptor variant is a null allele (Farrington et al. 2005). Based on the evidence and due to the potential impact of splice acceptor variants, the c.1187-2A>G variant is classified as likely pathogenic for MYH-associated polyposis.
Invitae RCV000338621 SCV000545702 pathogenic MYH-associated polyposis 2018-12-14 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 12 of the MUTYH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs587781628, ExAC 0.003%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in individuals affected with polyposis and/or colon/rectum cancer (PMID: 15931596, 15236166). In the one case with a confirmed adenocarcinoma of the colon or rectum, the two variants were confirmed to be in trans (PMID: 15931596). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as 9639A>G and IVS12-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 141282). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000480885 SCV000568579 pathogenic not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1187-2A>G or IVS12-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 12 of the MUTYH gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, also reported as MUTYH 9639A>G using an alternate transcript, has been reported in the compound heterozygous state with a second pathogenic variant in at least two individuals with colorectal cancer, one of whom also had 20-50 polyps (Wang 2004, Farrington 2005). Farrington et al. (2005) confirmed this variant to be in trans with a pathogenic variant in one patient with colorectal cancer and reported that this variant led to nonsense mediated mRNA decay by cDNA analysis utilizing patient RNA. Based on the currently available information, we consider MUTYH c.1187-2A>G to be pathogenic.
Color RCV000129730 SCV000685552 pathogenic Hereditary cancer-predisposing syndrome 2017-02-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000338621 SCV000711779 pathogenic MYH-associated polyposis 2016-03-18 criteria provided, single submitter clinical testing The c.1187-2A>G variant has been reported in 2 individuals with colorectal cance r (Wang 2004, Eliason 2005) and has also been identified in 2/65402 European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs587781628). However, this frequency is low enough to be consistent w ith the frequency of MUTYH-related attenuated familial adenomatous polyposis in the general population. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leadin g to an abnormal or absent protein. In summary, this variant meets criteria to b e classified as pathogenic for MUTYH-related attenuated familial adenomatous pol yposis in an autosomal recessive manner based upon its predict impact to the pro tein. ACMG/AMP criteria applied: PVS1, PM3, PS4_P.
Fulgent Genetics,Fulgent Genetics RCV000763341 SCV000894023 pathogenic MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2018-10-31 criteria provided, single submitter clinical testing

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