Submissions for variant NM_001048174.2(MUTYH):c.1102+1G>T

dbSNP: rs587781337

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000582433	SCV000690502	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-01-28	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +1 position of intron 12 of the MUTYH gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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 Likely Pathogenic.
Ambry Genetics	RCV000582433	SCV001170373	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-07-16	criteria provided, single submitter	clinical testing	The c.1186+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 12 of the MUTYH gene. This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001227829	SCV001400205	pathogenic	Familial adenomatous polyposis 2	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor 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 a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 492002). Studies have shown that disruption of this splice site results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (Invitae). This variant disrupts a region of the MUTYH protein in which other variant(s) (p.Leu388Pro) have been determined to be pathogenic (PMID: 16134147, 16941501, 17949294, 20848659, 23322991, 25820570). 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.