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

gnomAD frequency: 0.00001  dbSNP: rs587781628

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129730	SCV000184535	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-03	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 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 Laboratory Services, Illumina	RCV000338621	SCV000357894	likely pathogenic	Familial adenomatous polyposis 2	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	Familial adenomatous polyposis 2	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 12 of the MUTYH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 4 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs587781628, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with polyposis and/or colon/rectum cancer (PMID: 15236166, 15931596). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 9639A>G and IVS12-2A>G. ClinVar contains an entry for this variant (Variation ID: 141282). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 13 (Invitae). This variant disrupts a region of the MUTYH protein in which other variant(s) (p.Gly396Asp) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000480885	SCV000568579	pathogenic	not provided	2022-11-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21171015, 26202870, 25525159, 19725997, 19245865, 27194394, 24444654, 27096365, 15635083, 15236166, 27799157, 29490034, 31277343, 30787465, 18534194, 27145315, 15931596)
Color Diagnostics, LLC DBA Color Health	RCV000129730	SCV000685552	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-18	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, Mass General Brigham Personalized Medicine	RCV000338621	SCV000711779	pathogenic	Familial adenomatous polyposis 2	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	RCV002478389	SCV000894023	pathogenic	Familial adenomatous polyposis 2; Gastric cancer	2022-03-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000338621	SCV001361391	pathogenic	Familial adenomatous polyposis 2	2022-02-21	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: Four predict the variant abolishes a 3 prime acceptor site. Four predict the variant creates/strengthens an exonic cryptic 3 prime 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic (n=8) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000338621	SCV002017634	pathogenic	Familial adenomatous polyposis 2	2019-01-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000480885	SCV002049429	pathogenic	not provided	2021-05-03	criteria provided, single submitter	clinical testing	The MUTYH c.1187-2A>G variant (rs587781628), also known as IVS12-2A>G and 9639A>G, is reported in the literature in both the heterozygous and compound heterozygous states in individuals with MYH-associated polyposis (Church 2016, Eliason 2005, Farrington 2005, Wang 2004). This variant is also reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 141282). It is found in the general population with an overall allele frequency of 0.002% (7/281032 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron 12, and RNA analysis demonstrated transcripts with this splicing variant were absent, indicating this variant causes a null allele (Farrington 2005). Based on available information, this variant is considered to be pathogenic. REFERENCES Church J et al. The "Studded" Rectum: Phenotypic Evidence of MYH-Associated Polyposis. Dis Colon Rectum. 2016 Jun;59(6):565-9. PMID: 27145315. Eliason K et al. The potential for increased clinical sensitivity in genetic testing for polyposis colorectal cancer through the analysis of MYH mutations in North American patients. J Med Genet. 2005 Jan;42(1):95-6. PMID: 15635083. Farrington SM et al. Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet. 2005 Jul;77(1):112-9. PMID: 15931596. Wang L et al. MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology. 2004 Jul;127(1):9-16. PMID: 15236166.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480885	SCV002774364	pathogenic	not provided	2017-10-20	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-acceptor site and interferes with normal MUTYH mRNA splicing. In addition, this variant has been reported in individuals with colorectal cancer in the published literature (PMIDs: 15931596 (2005), 15635083 (2005), and 15236166 (2004)). A published RNA transcript analysis from a patient sample confirmed this variant causes loss of the wild-type transcript (PMID: 15931596 (2005)). Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV000338621	SCV004198826	pathogenic	Familial adenomatous polyposis 2	2023-10-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000338621	SCV004821945	pathogenic	Familial adenomatous polyposis 2	2023-12-13	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.