Submissions for variant NM_001048174.2(MUTYH):c.305-1G>C

gnomAD frequency: 0.00004  dbSNP: rs372267274

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221410	SCV000278764	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-24	criteria provided, single submitter	clinical testing	The c.389-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 5 of the MUTYH gene. This alteration has been identified as homozygous and in conjunction with other common pathogenic MUTYH mutations in multiple patients with 30-100 colorectal adenomas (Isidro G et al. Hum. Mutat. 2004 Oct;24:353-4; Torrezan GT et al. Orphanet J Rare Dis. 2013 Apr;8:54; Filipe B et al. Clin. Genet. 2009 Sep;76:242-55; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Of note, this alteration is also designated c.347-1G>C 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	RCV000230931	SCV000285947	pathogenic	Familial adenomatous polyposis 2	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with colorectal polyposis (PMID: 15366000, 17949294, 23561487; Invitae). 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 c.347-1G>C. ClinVar contains an entry for this variant (Variation ID: 234229). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 5 (Invitae). This variant disrupts a region of the MUTYH protein in which other variant(s) (p.Trp131Arg) have been determined to be pathogenic (PMID: 12853198, 19032956, 19394335, 19732775, 25820570, 26681312; 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.
Counsyl	RCV000230931	SCV000487337	pathogenic	Familial adenomatous polyposis 2	2016-02-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000478994	SCV000568584	pathogenic	not provided	2023-05-19	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 19725997, 19732775, 17949294, 12853198, 24470512, 15366000, 23561487, 19793053, 19032956, 33084842, 35264596, 33606809)
Color Diagnostics, LLC DBA Color Health	RCV000221410	SCV000685623	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 4 splice acceptor site of the MUTYH gene. This variant is also known as c.347-1G>C based on the NM_001048171.1 transcript. Although RNA studies have not been reported, this variant is expected to disrupt RNA splicing and result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with adenomatous polyposis in compound heterozygous state with pathogenic mutations (PMID: 12853198, 15366000, 17949294, 19032956, 19732775, 19793053, 23561487). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice acceptor site, c.389-1G>A and c.389-2A>G, are known to be disease-causing (Clinvar variation ID: 186819 and 215998). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000230931	SCV000697693	pathogenic	Familial adenomatous polyposis 2	2016-10-28	criteria provided, single submitter	clinical testing	Variant summary: The MUTYH c.389-1G>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant abolishes the 3' splicing acceptor site in intron 4. This variant is absent in 121386 control chromosomes, however, has been reported in numerous MAP patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics	RCV000230931	SCV000837780	pathogenic	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478994	SCV000888315	pathogenic	not provided	2017-12-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763342	SCV000894024	pathogenic	Familial adenomatous polyposis 2; Pilomatrixoma; Neoplasm of stomach	2018-10-31	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV000230931	SCV001424796	pathogenic	Familial adenomatous polyposis 2	2019-08-09	criteria provided, single submitter	clinical testing	The c.389-1G>C variant is predicted to lead to either nonsense-mediated mRNA decay or an abnormal protein product by destroying a canonical splice acceptor site. Loss-of-function variants in MUTYH are known to be pathogenic (Ali 2008, Nielsen 2011). The c.389-1G>C variant is not present in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). This variant has been reported in multiple individuals with MAP who are either homozygous or compound heterozygous for a second MUTYH pathogenic variant (Isidro 2004, Olschwang 2007, Torrezan 2013). Thus, this variant is interpreted as pathogenic.
Sema4, Sema4	RCV000221410	SCV002532283	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-10	criteria provided, single submitter	curation
Baylor Genetics	RCV000230931	SCV004198852	pathogenic	Familial adenomatous polyposis 2	2023-09-29	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353991	SCV000592682	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The c.389-1G>C variant was identified in 3 of 152 proband chromosomes (frequency: 0.020) from Portuguese and Brazilian individuals or families with MAP/AFAP/FAP (Isidro 2004, Torrezan 2013); however, control chromosomes were not evaluated in these studies. The c.389-1G>C variant was not identified in dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), database MutDB, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight VariantWire database, and COSMIC. The variant was identified in UMD (12x as a Causal variant), with co-occurring pathogenic MUTYH variants (including: c.494A>G and c.1145G>A). The c.389-1G>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence and this variant is the type of which could be expected to cause the disorder. 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 is classified as pathogenic.