Submissions for variant NM_001048174.2(MUTYH):c.606+1G>T

dbSNP: rs878854193

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230698	SCV000285961	likely pathogenic	Familial adenomatous polyposis 2	2023-05-27	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: 238352). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 8 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).
GeneDx	RCV000482610	SCV000571605	likely pathogenic	not provided	2016-09-07	criteria provided, single submitter	clinical testing	This variant is denoted MUTYH c.690+1G>T or IVS8+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 8 of the MUTYH gene. Although this variant destroys a canonical splice acceptor site and is predicted to cause abnormal splicing of exon 8, the skipping of exon 8 is predicted to be an in-frame event. While this particular variant has not, to our knowledge, been published in the literature, a nearby exonic variant, MUTYH c.690G>A, has been shown to result in skipping of exon 8 (Dallosso 2008). Importantly, Dellosso et al. (2008) reported that MUTYH c.690G>A has occurred in trans with MUTYH Tyr179Cys, one of the two common MUTYH pathogenic variants, in two individuals presenting with a phenotype consistent with MUTYH-Associated Polyposis (MAP), thus supporting that the skipping of exon 8 is deleterious. Based on the currently available information, we consider MUTYH c.690+1G>T to be a likely pathogenic variant.
Ambry Genetics	RCV002372265	SCV002667785	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-04-12	criteria provided, single submitter	clinical testing	The c.690+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 8 of 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 donor 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 mRNAdecay; 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 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	RCV000230698	SCV004198962	likely pathogenic	Familial adenomatous polyposis 2	2023-05-04	criteria provided, single submitter	clinical testing