ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.565C>T (p.Arg189Cys) (rs537292657)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163703 SCV000214277 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing The p.R217C variant (also known as c.649C>T), located in coding exon 8 of the MUTYH gene, results from a C to T substitution at nucleotide position 649. The arginine at codon 217 is replaced by cysteine, an amino acid with highly dissimilar properties. <span style="background-color:initial">This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.<span style="background-color:initial"> Since supporting evidence is limited at this time, the clinical significance of <span style="background-color:initial">this alteration<span style="background-color:initial"> remains unclear.
Counsyl RCV000410783 SCV000487333 uncertain significance MYH-associated polyposis 2016-01-18 criteria provided, single submitter clinical testing
Invitae RCV000410783 SCV000545731 uncertain significance MYH-associated polyposis 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 217 of the MUTYH protein (p.Arg217Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs537292657, ExAC 0.02%). This variant has been observed in an individual affected with multiple colorectal adenomas (PMID: 17949294), as well as in an individual affected with colorectal cancer (PMID: 28135145). This variant is also known as c.565C>T (p.Arg189Cys) and c.607C>T (p.Arg203Cys) in the literature. ClinVar contains an entry for this variant (Variation ID: 184447). 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 disruptive, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508296 SCV000601655 uncertain significance not specified 2017-04-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163703 SCV000685653 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-30 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 217 of the MUTYH protein. This variant is also known as NM_001048171.1:c.607C>T (p.Arg203Cys) and NM_001048174.2:c.565C>T (p.Arg189Cys) in the literature. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual each affected with colorectal cancer and polyposis (PMID: 17949294, 28135145). This variant has been identified in 12/251394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics RCV000410783 SCV000837769 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000508296 SCV000919795 uncertain significance not specified 2018-04-30 criteria provided, single submitter clinical testing Variant summary: MUTYH c.649C>T (p.Arg217Cys) results in a non-conservative amino acid change located in the HhH-GPD_domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. This frequency is lower than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (4.9e-05 vs 0.0046), allowing no conclusion about variant significance. The c.649C>T has been reported in the literature in individuals affected with multiple colorectal adenomas. These reports do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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