ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1103-2A>G (rs587781628)

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Total submissions: 9
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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 2018-08-09 criteria provided, single submitter clinical testing The c.1187-2A>G intronic pathogenic mutation results from an A to G substitution 2 nucleotides before coding exon 13 in the MUTYH gene. This alteration was reported in an individual who was diagnosed with colon cancer at age 38 and had 20-50 colon polyps, who also carried the well described MUTYH founder mutation p.G396D (also known as p.G382D) (Wang et al. Gastroenterology. 2004 Jul;127(1):9-16). In another study, this variant was reported in heterozygous form in a colon polyposis patient who previously tested negative for FAP and HNPCC (Eliason et al. J Med Genet. 2005 Jan;42(1):95-6). This variant has also been identified in the homozygous state and as compound heterozygous with MUTYH founder mutations in individuals with adenomatous polyposis (Ambry internal data). RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Note, this mutation is also referred to as c.1145-2A>G and IVS12-2A>G in some published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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 2020-10-25 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 Health, Inc RCV000129730 SCV000685552 pathogenic Hereditary cancer-predisposing syndrome 2020-11-09 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the -2 position of intron 12 of the MUTYH gene. This variant is also known as IVS12-2A>G and 9639A>G in the literature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study has reported this variant to result in a null allele (PMID: 15931596). This variant has been reported in three individuals affected with colorectal cancer and/or polyposis, including two individuals who were compound heterozygous with a known pathogenic variant (PMID: 15236166, 15931596, 27145315). This variant has been identified in 7/281032 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000338621 SCV000711779 pathogenic MYH-associated polyposis 2019-01-31 criteria provided, single submitter clinical testing The c.1187-2A>G variant has been reported in 2 individuals with colorectal cancer and/or polyps, one whom was compound heterozygous for this variant and a second pathogenic variant in MUTYH (Wang 2004, Eliason 2005). This variant has also been identified in 1/19908 East Asian chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org; dbSNP rs587781628). However, this frequency is low enough to be consistent with 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 leading to an abnormal or absent protein. In summary, this variant meets criteria to be classified as pathogenic for MUTYH-related attenuated familial adenomatous polyposis in an autosomal recessive manner based upon its predict impact to the protein. 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000338621 SCV001361391 pathogenic MYH-associated polyposis 2019-10-24 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1187-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3' acceptor site and four predict it creates/strengthens an exonic cryptic 3' acceptor site. One study reports experimental evidence in support of a deleterious effect of the variant, specifically demonstrating no expression of the variant allele following cDNA analysis in one patient (Farrington_2005). The variant allele was found at a frequency of 2.4e-05 in 249628 control chromosomes (gnomAD). c.1187-2A>G has been reported in the literature in individuals affected with MUTYH-associated Polyposis (e.g. Church_2016, Eliason_2005, Farrington_2005, Wang_2004). These data indicate that the variant is likely to be associated with disease. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (6 entries) and likely pathogenic (one entry). Based on the evidence outlined above, the variant was classified as pathogenic.

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