ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1239+1G>A

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002385722 SCV002690453 pathogenic Hereditary cancer-predisposing syndrome 2020-03-19 criteria provided, single submitter clinical testing The c.1323+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 13 of the MUTYH gene. This variant was identified in conjunction with a MUTYH founder mutation (p.Y179C) in a 29 year old female proband and her monozyoptic twin. The proband had approximately 30 colon polyps with the majority being tubulovillous adenomas and her sister had approximately 30 tubular adenomas (Casper M et al. Am. J. Gastroenterol., 2018 04;113:625-627). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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 RCV003120990 SCV003787313 pathogenic Familial adenomatous polyposis 2 2023-10-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 13 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with polyposis (external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1769939). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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