ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.397G>C (p.Asp133His) (rs564930066)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129002 SCV000172897 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-14 criteria provided, single submitter clinical testing The p.D161H variant (also known as c.481G>C), located in coding exon 6 of the MUTYH gene, results from a G to C substitution at nucleotide position 481. The aspartic acid at codon 161 is replaced by histidine, an amino acid with similar properties. This alteration was seen in a Chinese individual with a personal and family history of prostate cancer that underwent multi-gene panel testing (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). This amino acid position is not well 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.
Invitae RCV000204817 SCV000260661 uncertain significance MYH-associated polyposis 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 161 of the MUTYH protein (p.Asp161His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs564930066, ExAC 0.1%). This variant has been observed in individual(s) with MUTYH-associated polyposis (MAP) (Invitae), suspected of having Lynch syndrome (PMID: 25980754), and prostate cancer (PMID: 30093976). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 140814). 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. 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.
Counsyl RCV000204817 SCV000487330 uncertain significance MYH-associated polyposis 2015-12-30 criteria provided, single submitter clinical testing
GeneDx RCV000656908 SCV000565253 uncertain significance not provided 2018-07-02 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.481G>C at the cDNA level, p.Asp161His (D161H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAC>CAC). This variant has been observed in a cohort undergoing hereditary cancer panel testing for a personal and/or family history suspicious for Lynch syndrome (Yurgelun 2015). Additionally, MUTYH Asp161His has been identified in an individual reported to have MUTYH-Associated Polyposis where tumor tissue was found to be enriched for C:G>A:T transversions (Weren 2015). MUTYH Asp161His was observed at an allele frequency of 0.05% (16/34,394) in individuals of Latino ancestry in large population cohorts (Lek 2016). MUTYH Asp161His is not located in a known functional domain. 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 Asp161His is pathogenic or benign. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481844 SCV000601649 uncertain significance not specified 2017-05-19 criteria provided, single submitter clinical testing
Mendelics RCV000204817 SCV000837777 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656908 SCV000888317 uncertain significance not provided 2017-11-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129002 SCV000902780 likely benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656908 SCV001147272 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing

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