ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.545G>C (p.Arg182Pro) (rs143353451)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000807417 SCV000947466 uncertain significance MYH-associated polyposis 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 182 of the MUTYH protein (p.Arg182Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MUTYH-related disease. 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. This variant disrupts the p.Arg182 amino acid residue in MUTYH. Other variant that disrupts this residue have been observed in affected individuals (PMID: 15366000, 16557584, 20618354, 19394335, 19032956), suggesting that it is a clinically significant residue. The p.Arg182His variant is also known as R154H and R168H in the literature. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Ambry Genetics RCV001024139 SCV001186106 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-30 criteria provided, single submitter clinical testing The p.R182P variant (also known as c.545G>C), located in coding exon 7 of the MUTYH gene, results from a G to C substitution at nucleotide position 545. The arginine at codon 182 is replaced by proline, an amino acid with dissimilar properties. A different alteration at this position, p.R182H, has been identified in trans in several individuals with MAP phenotypes and has been determined to be functionally deficient (Isidro et al. Hum Mutat 2004 Oct; 24(4):353-4; Di Gregorio et al. Gastroenterology 2006 Aug; 131(2):439-44; Aretz et al. Int J Cancer 2006 Aug 15;119(4): 807-14; Jones N et al. Gastroenterology. 2009 Aug;137(2):489-94, 494.e1; Morak M et al. Clin Genet. 2010 Oct;78(4):353-63; Goto et al. Hum Mutat 2010 Nov; 31(11):E1861-74; Komine K et al. Hum. Mutat., 2015 Jul;36:704-11). This amino acid position is highly conserved in available vertebrate species. In addition, p.R182P is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on internal structural analysis, this variant is more disruptive than known pathogenic variants (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285700 SCV001472176 uncertain significance none provided 2019-08-28 criteria provided, single submitter clinical testing The MUTYH c.545G>C; p.Arg182Pro variant, to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 651962). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 182 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (His, Cys, Gly) have been reported in individuals with MUTYH-associated polyposis, and the p.Arg182His variant, also known as R154H (NM_001048174) and R168H (NM_001048171), is considered pathogenic (Aretz 2006, Isidro 2004, Morak 2010, Tricarico 2011). However, given the lack of clinical and functional data, the significance of the p.Arg182Pro variant is uncertain at this time. References: Aretz S et al. MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer. 2006 Aug 15;119(4):807-14. Isidro G et al. Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas. Hum Mutat. 2004 Oct;24(4):353-4. Morak M et al. MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. Clin Genet. 2010 Oct;78(4):353-63. Tricarico R et al. High resolution melting analysis for a rapid identification of heterozygous and homozygous sequence changes in the MUTYH gene. BMC Cancer. 2011 Jul 21;11:305.

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