Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000198184 | SCV000253703 | pathogenic | Familial adenomatous polyposis 2 | 2022-08-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 215998). This variant is also known as c.347-2A>G. Disruption of this splice site has been observed in individuals with colorectal polyposis (PMID: 15366000, 19732775; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the MUTYH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). |
| Ambry Genetics | RCV002354561 | SCV002623561 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-12-01 | criteria provided, single submitter | clinical testing | The c.389-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 5 in the MUTYH gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. 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). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant was identified in the homozygous state in a study that looked at the phenotypic spectrum of MUTYH-Associated Polyposis (MAP) in the context of multi-gene hereditary cancer panel testing (Sutcliffe EG et al. Fam. Cancer, 2019 04;18:203-209). Two other alterations that affect the same canonical splice acceptor site, c.389-1G>A and c.389-1G>C, have been reported as pathogenic based on being identified in conjunction with MUTYH pathogenic mutations in 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; 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Baylor Genetics | RCV000198184 | SCV004199436 | pathogenic | Familial adenomatous polyposis 2 | 2021-11-22 | criteria provided, single submitter | clinical testing |