ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.393G>A (p.Trp131Ter) (rs587781295)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128998 SCV000172893 pathogenic Hereditary cancer-predisposing syndrome 2019-07-13 criteria provided, single submitter clinical testing The p.W131* pathogenic mutation (also known as c.393G>A), located in coding exon 5 of the MUTYH gene, results from a G to A substitution at nucleotide position 393. This changes the amino acid from a tryptophan to a stop codon within coding exon 5. This pathogenic mutation was identified in a proband who underwent hereditary cancer multigene panel testing (LaDuca H et al. Genet. Med. 2014 Nov;16:830-7; LaDuca H et al. PLoS ONE 2017 Feb;12:e0170843). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000521741 SCV000617564 pathogenic not provided 2017-06-26 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.393G>A at the cDNA level and p.Trp131Ter (W131X) atthe protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon(TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual referred for clinical testing for inheritedcancer (LaDuca 2014). We consider it to be pathogenic
Color Health, Inc RCV000128998 SCV000690572 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001068416 SCV000919792 likely pathogenic MYH-associated polyposis 2017-09-15 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.393G>A (p.Trp131X) variant is a nonsense change that results in the loss of the ~419 amino acids of MUTYH protein (~75%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.508delG, p.Val170X; c.1147delC, p.Ala385fsX23; c.1227_1228dupGG, p.Glu410fsX43). One in silico tool predicts a damaging outcome for this variant. The variant is absent from the large control population datasets of ExAC and gnomAD (~25184 and 246196 chrs tested, respectively). This variant has been reported in at least one affected individuals via a published report (LaDuca_2014). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Invitae RCV001068416 SCV001233528 pathogenic MYH-associated polyposis 2019-11-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp131*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) referred for genetic testing for hereditary cancer (PMID: 24763289). ClinVar contains an entry for this variant (Variation ID: 140811). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.

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