ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.37-5T>G (rs876660715)

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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 RCV000219910 SCV000278357 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-07 criteria provided, single submitter clinical testing The c.37-5T>G intronic variant results from a T to G substitution 5 nucleotides upstream from coding exon 2 in the MUTYH gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000481124 SCV000567285 uncertain significance not provided 2016-04-28 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.37-5T>G or IVS1-5T>G and consists of a T>G nucleotide substitution at the -5 position of intron 1 of the MUTYH gene. Multiple in silico models predict this variant to damage the nearby natural acceptor site and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH c.37-5T>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The thymine (T) nucleotide that is altered is conserved through mammals. Based on currently available information, it is unclear whether MUTYH c.37-5T>G is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000547282 SCV000639316 uncertain significance MYH-associated polyposis 2019-08-14 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the MUTYH gene. It does not directly change the encoded amino acid sequence of the MUTYH protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 233892). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant has uncertain impact on MUTYH function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000219910 SCV000911621 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192931 SCV001361393 uncertain significance not specified 2019-10-10 criteria provided, single submitter clinical testing Variant summary: MUTYH c.37-5T>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.37-5T>G in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.6952C>T, p.Arg2318X; internal sample). Four ClinVar submissions (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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