Submissions for variant NM_001128425.2(MUTYH):c.933_933+1del

dbSNP: rs1553127514

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564810	SCV000666452	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-05-02	criteria provided, single submitter	clinical testing	The c.933_933+1delAG variant results from a deletion of 1 nucleotide located at position 933 as well as a deletion of the first intronic nucleotide after coding exon 10 of the MUTYH gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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	RCV001208903	SCV001380315	pathogenic	Familial adenomatous polyposis 2	2023-07-07	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 481788). 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. This variant is also known as c.933_933+1del. 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 creates a premature translational stop signal (Splice site) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686).
Color Diagnostics, LLC DBA Color Health	RCV000564810	SCV004358576	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-12-15	criteria provided, single submitter	clinical testing	This variant deletes the last nucleotide of exon 10 and the +1 nucleotide of intron 10 in the MUTYH gene. Splice site prediction tools suggest 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. Based on the available evidence, this variant is classified as Likely Pathogenic.