ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1261C>T (p.His421Tyr) (rs141432759)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129005 SCV000172901 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-07 criteria provided, single submitter clinical testing The p.H435Y variant (also known as c.1303C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1303. The histidine at codon 435 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000587968 SCV000211417 uncertain significance not provided 2018-05-04 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1303C>T at the cDNA level, p.His435Tyr (H435Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH His435Tyr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the NUDIX domain (Ruggieri 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MUTYH His435Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two MUTYH pathogenic variants on opposite chromosomes.
Counsyl RCV000410796 SCV000487350 uncertain significance MYH-associated polyposis 2016-04-20 criteria provided, single submitter clinical testing
Invitae RCV000410796 SCV000639271 uncertain significance MYH-associated polyposis 2020-10-06 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 435 of the MUTYH protein (p.His435Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs141432759, ExAC 0.02%). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 140816). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000129005 SCV000685564 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587968 SCV000697665 uncertain significance not provided 2015-12-23 criteria provided, single submitter clinical testing

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