ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.206G>A (p.Arg69Gln) (rs755653922)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164952 SCV000215643 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-02 criteria provided, single submitter clinical testing The p.R97Q variant (also known as c.290G>A), located in coding exon 3 of the MUTYH gene, results from a G to A substitution at nucleotide position 290. The arginine at codon 97 is replaced by glutamine, an amino acid with highly similar properties. This alteration, designated as p.R94Q, has been detected in conjunction with a MUTYH founder mutation (phase unknown) in a patient diagnosed with early-onset colon cancer and bilateral breast cancer, as well as a family history of breast, colon, and uterine cancer, who had previously tested negative for mutations in BRCA1/2 by sequencing (Maxwell KN et al. Genet Med. 2015 Aug;17(8):630-8). This amino acid position is well 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.
Invitae RCV000555612 SCV000639305 likely benign MYH-associated polyposis 2020-12-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164952 SCV000690551 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000612945 SCV000713067 uncertain significance not specified 2020-04-09 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000612945 SCV000919789 uncertain significance not specified 2017-10-31 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.290G>A (p.Arg97Gln) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/246266 control chromosomes at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). It has been reported in multiple affected individuals without strong evidence for causality (Maxwell_2014, Ricci_MUTYH_2016, Tung_2014). In addition, one other clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354534 SCV001549177 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Arg97Gln variant was not identified in the literature nor was it identified in the COSMIC, Zhejiang Colon Cancer (LOVD), COGR, or UMD database. The variant was identified in dbSNP (ID: rs755653922) as “With Uncertain significance allele” and the Exome Aggregation Consortium database (August 8, 2016) in 1 of 121384 chromosomes (frequency: 0.000008). The variant was identified in the European (Non-Finnish) population in 1 of 66722 chromosomes (frequency: 0.00001), but not in the African, East Asian, Finnish, Latino, South Asian or Other populations. In Clinvar and Clinvitae, the variant was identified as uncertain significance by Ambry Genetics; InSiGHT Colon Cancer Gene Variant Database (LOVD) 1x as unknown. The p.Arg97 residue is not 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 amino acid Glutamine (Gln) is present in cow, increasing the likelihood that this variant does not have clinical significance. 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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