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

dbSNP: rs372267274

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166470	SCV000217267	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-28	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. 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This pathogenic mutation has been identified in conjunction with a MUTYH founder mutation in at least 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; Guarinos C et al. Clin Cancer Res 2014 Mar;20(5):1158-68). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469315	SCV000545764	pathogenic	Familial adenomatous polyposis 2	2023-11-14	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 individuals with colorectal cancer and multiple polyposis (PMID: 12853198, 19032956, 19732775, 24470512). This variant is also known as c.347-1G>A. ClinVar contains an entry for this variant (Variation ID: 186819). 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.
Color Diagnostics, LLC DBA Color Health	RCV000166470	SCV000685622	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the canonical -1 position of intron 4 splice acceptor of the MUTYH gene. This is also know as IVS4-1G>A and c.347-1G>A based on an alternative MUTYH transcript (NM_001048171). Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed by published RNA studies, this variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with adenomatous polyposis and/or colorectal cancer together with another known pathogenic variant in the same gene (PMID: 12853198, 19732775, 24470512; communication with an external laboratory, ClinVar SCV000545764.5; Color internal data). Compound heterozygosity consistent with autosomal recessive inheritance has been reported in three of these probands (PMID: 12853198, 19732775, 24470512). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Revvity Omics, Revvity	RCV000469315	SCV002017638	pathogenic	Familial adenomatous polyposis 2	2019-06-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000469315	SCV004198849	pathogenic	Familial adenomatous polyposis 2	2024-02-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000469315	SCV004829464	pathogenic	Familial adenomatous polyposis 2	2024-02-05	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the canonical -1 position of intron 4 splice acceptor of the MUTYH gene. This is also know as IVS4-1G>A and c.347-1G>A based on an alternative MUTYH transcript (NM_001048171). Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed by published RNA studies, this variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with adenomatous polyposis and/or colorectal cancer together with another known pathogenic variant in the same gene (PMID: 12853198, 19732775, 24470512; communication with an external laboratory, ClinVar SCV000545764.5; Color internal data). Compound heterozygosity consistent with autosomal recessive inheritance has been reported in three of these probands (PMID: 12853198, 19732775, 24470512). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000469315	SCV005045788	pathogenic	Familial adenomatous polyposis 2	2018-07-24	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000469315	SCV005402206	pathogenic	Familial adenomatous polyposis 2	2024-02-06	criteria provided, single submitter	clinical testing	The MUTYH c.389-1G>A intronic change results in a G to A substitution at the -1 position of intron 4 of the MUTYH gene. This variant is predicted to result in aberrant splicing. This variant has been reported in conjunction with another pathogenic variant in individuals with adenomas (PMID: 19732775, 24470512). This variant is also absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.
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.