ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1033C>A (p.Pro345Thr) (rs587782773)

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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 RCV000132303 SCV000187388 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-03 criteria provided, single submitter clinical testing The p.P359T variant (also known as c.1075C>A), located in coding exon 12 of the MUTYH gene, results from a C to A substitution at nucleotide position 1075. The proline at codon 359 is replaced by threonine, an amino acid with highly similar properties. This variant has been reported in the literature as an undefined rare variant that was identified in combination with another MUTYH mutation in a patient who had colorectal cancer diagnosed under the age of sixty with at least two affected family members; however, phase for the two variants (whether in cis or trans) was not determined (Cheadle JP and Sampson JR. DNA Repair (Amst.) 2007 Mar; 6(3):274-9). This alteration was also identified in an individual in conjunction with the p.Y179C MUTYH pathogenic variant; however, phase for the two variants was not determined. Furthermore, the individual in which these two MUTYH variants were identified met Amsterdam I criteria for Lynch syndrome, but had normal mismatch repair (MMR) function by tumor testing which demonstrated microsatellite stability and/or normal expression of the four MMR proteins (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). Of note, this alteration is also designated as c.1033C>A (p.P345T) in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000411922 SCV000487368 uncertain significance MYH-associated polyposis 2016-08-08 criteria provided, single submitter clinical testing
Invitae RCV000411922 SCV000545747 uncertain significance MYH-associated polyposis 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 359 of the MUTYH protein (p.Pro359Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs587782773, ExAC 0.005%). This variant has been observed in individuals with MUTYH-related disease (PMID: 17161978, 17581577, 28944238). It is also known as P345T in the literature. ClinVar contains an entry for this variant (Variation ID: 142860). 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. 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 RCV000132303 SCV000690497 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780503 SCV000917808 uncertain significance not specified 2018-09-28 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1075C>A (p.Pro359Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.5e-05 in 275480 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1075C>A has been reported in the literature in an individual affected with MUTYH-associated Polyposis (DeRycke_2017). This report does not provide an unequivocal conclusion about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (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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