ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.616G>A (p.Val206Met) (rs200165598)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123153 SCV000166457 uncertain significance MYH-associated polyposis 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 234 of the MUTYH protein (p.Val234Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs200165598, ExAC 0.02%). This variant has been observed in individuals and families affected with colon cancer and/or clinical features of MUTYH-associated polyposis (MAP) (PMID: 16774938, 14991577, 30374176). This variant is also known as c.658G>A (p.Val220Met) in the literature. ClinVar contains an entry for this variant (Variation ID: 135989). Experimental studies have shown that this missense change partially impairs MUTYH protein function (PMID: 25820570, 26694661). 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 RCV000131773 SCV000186820 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-29 criteria provided, single submitter clinical testing <span style="background-color:initial">The p.V234M variant (also known as c.700G>A), located in exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 700. The valine at codon 234 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in the heterozygous state in early-onset colorectal cancer and HNPCC/HNPCC-like cohorts to date (Peterlongo P et al. Carcinogenesis. 2006 Nov;27:2243-9; Fleischmann C et al. Int. J. Cancer. 2004 Apr;109:554-8). In two studies, it was reported to have at least partial function in bacterial and human cell-line based glycosylase and mutagenesis assays (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11; Shinmura K et al. Hum. Mutat. 2016 Apr;37:350-3). This variant segregated with colon cancer or colon polyps in five siblings reported to have co-occurrence with a pathogenic MUTYH founder mutation, which was confirmed to be in trans through familial testing (Tsai GJ et al. Genet. Med. 2019 06;21:1435-1442). This variant has also been identified in conjunction with likely pathogenic or pathogenic MUTYH variants in individuals with colonic polyposis and is likely to be in trans given it co-occurs with multiple different likely pathogenic or pathogenic variants (Ambry internal data). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (Ambry internal data; Guan Y et al. Nat. Struct. Biol. 1998 Dec;5:1058-64; Manuel RC et al. J. Biol. Chem. 2004 Nov;279:46930-9). Of note, t<span style="background-color:initial">his variant is also designated as V220M in published literature.​ <span style="background-color:initial">This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000586141 SCV000211403 likely pathogenic not provided 2021-05-06 criteria provided, single submitter clinical testing Published functional studies are conflicting: partially defective base excision repair activity, but DNA glycosylase activity and mutation suppression ability similar to wild-type (Komine 2015, Shinmura 2016); Observed as heterozygous in individuals with colon cancer as well as in healthy controls (Fleischmann 2004, Peterlongo 2006, DeRycke 2017); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as Val220Met and Val206Met; This variant is associated with the following publications: (PMID: 19725997, 14991577, 16774938, 25820570, 15465463, 25980754, 26694661, 28944238, 30374176, 33436027)
Counsyl RCV000123153 SCV000487314 uncertain significance MYH-associated polyposis 2015-11-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212704 SCV000601657 uncertain significance not specified 2017-03-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131773 SCV000685660 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-25 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 234 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies have been inconsistent regarding the ability of this variant to impair MUTYH function (PMID: 25820570, 26694661). This variant has been reported in individuals affected with colorectal cancer and polyposis in the literature (PMID: 14991577, 16774938, 25980754, 30374176). In one family the variant has been found in trans to the pathogenic MUTYH p.Tyr179Cys in 5 siblings with colon cancer and/or multiple colon polyps, indicating the variant may be deleterious (PMID: 30374176). This variant has been identified in 24/282044 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586141 SCV000697707 uncertain significance not provided 2016-12-05 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212704 SCV000712773 uncertain significance not specified 2020-05-22 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
University of Washington Department of Laboratory Medicine, University of Washington RCV000123153 SCV000788256 likely pathogenic MYH-associated polyposis 2018-02-16 criteria provided, single submitter research The MUTYH variant designated as NM_001128425.1:c.700G>A (p.Val234Met) is classified as likely pathogenic. In one observed family, this variant co-occurs with a known pathogenic variant (MUTYH p.Tyr179Cys or p.Y179C) in MUTYH in five siblings who each have a documented history of multiple colon polyps and/or colon cancer. The variant was shown to be in trans configuration with the MUTYH p.Y179C variant. This genomic position is highly conserved. Experimental studies of this variant have shown that it partially impairs MUTYH protein function (Komine 2015, PMID: 25820570). This variant is listed in population databases and is present in 1/5500 individuals of European descent ( Bayesian analysis integrating all of this data (Tavtigian et al, 2018) gives about 98% probability of pathogenicity, which is consistent with a classification of likely pathogenic. MUTYH p.Val234Met is expected to alter MUTYH function and increase the risk of developing colon cancer, multiple colon polyps, and other features of MYH-associated polyposis when it co-occurs with a pathogenic mutation in MUTYH (Morak 2010, PMID 20618354; Grover 2012, PMID: 22851115). This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
PreventionGenetics,PreventionGenetics RCV000586141 SCV000806366 uncertain significance not provided 2017-07-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586141 SCV000889534 uncertain significance not provided 2020-02-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000212704 SCV001159672 uncertain significance not specified 2019-05-04 criteria provided, single submitter clinical testing The MUTYH c.700G>A; p.Val234Met variant (rs200165598), also known as Val220Met for traditional nomenclature, is reported in the literature in individuals with colorectal cancer but a second MUTYH variant was not identified (Fleischmann 2004, Peterlongo 2006, Yurgelun 2015). Our laboratory has identified this variant previously in an individual with a personal and family history of colon cancer, who also carried a pathogenic MUTYH frameshift variant. One functional study shows that the p.Val234Met variant protein has partially defective function (Komine 2015), while another study shows the variant protein retains normal repair activity (Shinmura 2016). This variant is reported in ClinVar (Variation ID: 135989). It is found in the general European (non-Finnish) population with an allele frequency of 0.02% (23/128662 alleles) in the Genome Aggregation Database. Due to limited information, the significance of this variant is uncertain at this time. REFERENCES Fleischmann C et al. Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer. Int J Cancer. 2004 Apr 20;109(4):554-8. Komine K et al. Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain. Hum Mutat. 2015 Jul;36(7):704-11. Peterlongo P et al. Increased frequency of disease-causing MYH mutations in colon cancer families. Carcinogenesis. 2006 Nov;27(11):2243-9. Shinmura K et al. Functional Evaluation of Nine Missense-Type Variants of the Human DNA Glycosylase Enzyme MUTYH in the Japanese Population. Hum Mutat. 2016 Apr;37(4):350-3. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20.

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