ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1424G>A (p.Gly475Glu) (rs3219494)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130413 SCV000185275 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-02 criteria provided, single submitter clinical testing The p.G503E variant (also known as c.1508G>A), located in coding exon 15 of the MUTYH gene, results from a G to A substitution at nucleotide position 1508. The glycine at codon 503 is replaced by glutamic acid, an amino acid with similar properties. This alteration was reported as a germline variant of uncertain significance in a cohort of 1260 individuals undergoing Lynch syndrome testing (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). This alteration has also been reported in an individual with endometrial cancer from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec;6:10086). Complementation studies using MutY-disrupted E. coli indicated that this alteration resulted in partially defective protein function (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000585961 SCV000211393 uncertain significance not provided 2018-07-18 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1508G>A at the cDNA level, p.Gly503Glu (G503E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGG>GAG). MUTYH Gly503Glu was identified in at least one individual with endometrial cancer as well as in an individual undergoing multigene cancer panel testing due to a personal history of a Lynch syndrome-related cancer and/or polyps (Lu 2015, Yurgelun 2015). Functional analysis found this variant to cause partially defective base excision repair activity in comparison to wild type (Komine 2015). MUTYH Gly503Glu was observed at an allele frequency of 0.22% (51/23,122) in individuals of African 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 Gly503Glu 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 pathogenic variants on opposite chromosomes in MUTYH.
Invitae RCV000195990 SCV000254706 uncertain significance MYH-associated polyposis 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 503 of the MUTYH protein (p.Gly503Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs3219494, ExAC 0.2%). This variant has been reported in individuals with endometrial cancer (PMID: 26689913) and suspected Lynch syndrome (PMID: 25980754). This variant is also known as c.1466G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 134866). An experimental study has shown that this missense change does not significantly affect MUTYH protein function (PMID: 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.
Counsyl RCV000195990 SCV000487348 uncertain significance MYH-associated polyposis 2016-04-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130413 SCV000685590 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-17 criteria provided, single submitter clinical testing This missense variant replaces glycine with glutamic acid at codon 503 of the MUTYH protein. This variant is also known as c.1466G>A (p.Gly489Glu) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported this variant as causing partial loss of MUTYH function in an bacterial complementation assay (PMID: 25820570). This variant has been reported in an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 60/274602 chromosomes (56/24032 African 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 RCV000585961 SCV000697681 uncertain significance not provided 2017-02-02 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.1508G>A (p.Gly503Glu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 16/84660 control chromosomes (1 homozygote) at a frequency of 0.000189, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). In addition, this observation needs to be cautiously considered due to ExAC indicating the area to be a possible "low-quality" site. The variant of interest has been reported in affected individuals via publications, along with a functional study indicating the variant may affect MUTYH protein function. In addition, multiple reputable clinical laboratories cite the variant with a classification of "uncertain significance." Taken together, this variant is classified as VUS.
Mendelics RCV000195990 SCV000837744 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585961 SCV000889525 uncertain significance not provided 2020-05-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000121600 SCV000966236 uncertain significance not specified 2018-07-25 criteria provided, single submitter clinical testing The p.Gly503Glu variant in MUTYH has been reported in one individual with clinic al features of Lynch Syndrome as well as in one young reportedly healthy individ ual (Bodian 2014). This variant has also been reported by other clinical laborat ories in Clinvar (Variation ID: 134866) and has been identified in 0.22% (51/231 22) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs3219494). Although this variant has been seen i n the general population, its frequency is not high enough to rule out a pathoge nic role. In vitro functional studies provide some evidence that the p.Gly503Glu variant may impact protein function (Komine 2015). Additionally, computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p .Gly503Glu variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting.
Illumina Clinical Services Laboratory,Illumina RCV000195990 SCV001257603 uncertain significance MYH-associated polyposis 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Baylor Genetics RCV000195990 SCV001481597 uncertain significance MYH-associated polyposis 2020-01-22 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
ITMI RCV000121600 SCV000085797 not provided not specified 2013-09-19 no assertion provided reference population

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