ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.583A>G (p.Ile195Val) (rs200872702)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586038 SCV000149678 uncertain significance not provided 2018-08-17 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.667A>G at the cDNA level, p.Ile223Val (I223V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant, also published as Ile195Val or Ile209Val, co-occurred with the pathogenic MUTYH founder variant p.Tyr179Cys in an individual with multiple adenomas and colorectal cancer and has been observed as a single variant in at least three individuals with early-onset colon cancer and/or more than 10 polyps (Russell 2006, Morak 2011, Marabelli 2016, Ricci 2017). It was also reported in an individual with personal/family history suspicious for hereditary breast and ovarian cancer, but in another breast cancer kindred, did not appear to segregate with disease (Hilbers 2013, Maxwell 2016). In vitro functional studies have found that this variant leads to partially reduced glycosylase activity, while an in vivo complementation assay detected mutation rates comparable to wild type (Goto 2010, Komine 2015). MUTYH Ile223Val was observed at an allele frequency of 0.03% (43/126,640) in individuals of European ancestry in large population cohorts (Lek 2016). This variant 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 Ile223Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two MUTYH pathogenic variants on opposite chromosomes.
Ambry Genetics RCV000115769 SCV000186058 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-01 criteria provided, single submitter clinical testing The p.I223V variant (also known as c.667A>G), located in coding exon 8 of the MUTYH gene, results from an A to G substitution at nucleotide position 667. The isoleucine at codon 223 is replaced by valine, an amino acid with highly similar properties. This alteration was first described in a 54-year-old female with 100-1000 polyps and osteosarcoma who had no personal or family history of colorectal cancer. This patient was not found to have a second MUTYH alteration or an APC alteration (Sieber OM et al. N. Engl. J. Med. 2003 Feb;348:791-9). In another study, this alteration was detected in a 36-year-old female with colon cancer who also had a splice-site mutation in the OGG1 gene (c.137G>C). The MUTYH alteration was detected in the patient's mother and one maternal aunt, both of whom had adenomas in their sixties (one and two adenomas, respectively), and in a maternal aunt who had colon cancer at age 56. The patient's father, who had one benign polyp at age 65, carried the OGG1 mutation. The OGG1 gene is involved in the base excision repair pathway and authors suggest that it may be involved in familial polyposis or colorectal cancer (Morak M et al. Eur. J. Cancer. 2011 May;47:1046-55). The MUTYH p.I223V alteration has been reported to exhibit slightly lower glycosylation activity (66.9%) compared to wildtype (100%) and has been described as partially defective (Goto M et al. Hum. Mutat. 2010 Nov;31:E1861-74; Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). This alteration has also been identified in patients with prostate cancer, pancreatic cancer, breast and/or ovarian cancer with no co-occurring variants in MUTYH reported (Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-817; Brovkina OI et al. Front Oncol, 2018 Oct;8:421; Scarpa A et al. Nature, 2017 03;543:65-71; Isaacsson Velho P et al. Prostate, 2018 04;78:401-407). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Of note, this alteration is also designated as p.I209V (c.625A>G) and p.I195V in published literature. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000197617 SCV000254713 uncertain significance MYH-associated polyposis 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 223 of the MUTYH protein (p.Ile223Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs200872702, ExAC 0.03%). This variant has been observed in individuals with colorectal polyposis, colon cancer, breast cancer, prostate cancer, and individuals undergoing hereditary cancer predisposition testing (PMID: 16287072, 12606733, 17949294, 21195604, 20618354, 27705013, 29368341, 23383274, 31285513, 31214250, 31159747). ClinVar contains an entry for this variant (Variation ID: 127847). This variant has been reported to have conflicting or insufficient data to determine the effect on MUTYH protein function (PMID: 20848659, 25820570). 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 RCV000115769 SCV000537585 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-07 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 223 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant causes a mild reduction in MUTYH activity in an enzymatic assay (PMID: 20848659), but could complement the functional deficiency of MutY-null bacteria (PMID: 25820570). This variant has been reported in individuals affected with adenomatous polyposis, colorectal adenomas, colon cancer, breast and/or ovarian cancer, and prostate cancer (PMID: 16287072, 12606733, 17949294, 21195604, 20618354, 27705013, 29368341, 30333958, 30680046, 31285513). All reported probands were heterozygous for this variant. This variant has also been identified in 57/282728 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 RCV000212703 SCV000697704 uncertain significance not specified 2020-06-02 criteria provided, single submitter clinical testing Variant summary: MUTYH c.667A>G (p. Ile223Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silicon tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 252250 control chromosomes, predominantly at a frequency of 0.00037 within the Non-Finnish European subpopulation in the nomad database. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis, allowing no conclusion about variant significance. In a comprehensive literature review spanning 16 years (2003-2019), c.667A>G has been widely reported in the literature in sequencing studies of individuals affected with breast cancer, APC-negative polyposis, attenuated polyposis, as a non-reportable incidental finding in settings of WES, in compound heterozygosity with another MUTYH variant in a colorectal cancer patient with an autosomal dominant family history, with a medium penetrance MUTYH variant in a colorectal cancer patient (example, Hilbers_2013, Sieber_2003, Russell_2006, Olschwang_2007, Morak_2010, Morak_2011, Jurgens_2015, Marabelli_2016, Tung_2015, Lorca_2019, Henn_2019). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. At-least one co-occurrence with another pathogenic variant has been reported (BRCA2 c.8537_8538del, p. Glu2846Glyfs*22) in a patient with breast cancer, providing supporting evidence for a benign role (Tung_2015). At-least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a moderate impairment of adenine DNA glycosylase activity (Goto_2010) which is contrasted by a normal activity in a functional complementation assay in E. coli (Komine_2015). Twelve 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. Some submitters have cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was evaluated to retain its classification as uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212703 SCV000711972 uncertain significance not specified 2017-01-25 criteria provided, single submitter clinical testing The p.Ile223Val variant in MUTYH has been reported in 4 individuals with adenoma tous polyposis as well as in 3 affected relatives from 1 family (Sieber 2003, Ru ssell 2006, Morak 2010, Morak 2011). However, no second MUTYH variant was detect ed in any of the affected individuals. This variant has been identified in 43/12 6744 of European chromosomes by the Genome Aggregation Database (gnomAD, http://; dbSNP rs200872702). In vitro functional studies are conflicting with one study suggesting partial impact on protein function and ano ther study suggesting no impact (Goto 2010, Komine 2015). However, these types o f assays may not accurately represent biological function. Additionally, computa tional prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance o f the p.Ile223Val variant is uncertain.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000197617 SCV000781799 uncertain significance MYH-associated polyposis 2016-11-01 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115769 SCV000822077 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000197617 SCV000837767 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586038 SCV000888322 uncertain significance not provided 2019-04-11 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586038 SCV001147270 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000197617 SCV001257408 uncertain significance MYH-associated polyposis 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
True Health Diagnostics RCV000115769 SCV000788073 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-12 no assertion criteria provided clinical testing
Molecular Oncology Laboratory,Hospital Clínico San Carlos RCV000197617 SCV000844930 uncertain significance MYH-associated polyposis 2018-06-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358471 SCV001554213 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Ile223Val variant was identified in 3 of 878 proband chromosomes (frequency: 0.003) from individuals or families with colorectal adenomas, FAP, or classic polyposis and was not identified in 214 control chromosomes from healthy individuals (Oliver 2003, Olschwang 2007, Russell 2006). The variant was also identified in dbSNP (ID: rs200872702) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and nine other submitters), and in UMD-LSDB (1x as unclassified variant). The variant was identified in control databases in 55 of 277080 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23992 chromosomes (freq: 0.00004), Other in 4 of 6462 chromosomes (freq: 0.0006), Latino in 4 of 34418 chromosomes (freq: 0.0001), European in 43 of 126640 chromosomes (freq: 0.0003), Ashkenazi Jewish in 1 of 10152 chromosomes (freq: 0.0001), South Asian in 2 of 30782 chromosomes (freq: 0.00007), while the variant was not observed in the East Asian, and Finnish populations. To understand the functional consequences of this variant, 47 MUTYH gene variants were generated via site-directed mutagenesis, expressed in MutY - disrupted Escherichia coli, and assessed for their ability to complement the functional deficiency in the E. coli by monitoring spontaneous mutation rates (Komine, 2015). The p.Ile223Val variant retained function but was only partially active in the glycosylase assay. In addition, Morak et al. describe evidence for digenic inheritance in hereditary colorectal cancer with mutations in the base excision repair genes. In a single case, a germline paternal mutation in OGG1, in combination with a maternal MUTYH p.Ile223Val mutation was identified in a female patient with advanced synchronous colon cancer and adenomas at the age of 36 years. This could point towards digenic inheritance for colorectal cancer (CRC) predisposition (Morak 2011), although this remains a single case. The p.Ile223 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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