ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.848G>A (p.Arg283Lys) (rs149342980)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590230 SCV000211412 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.932G>A at the cDNA level, p.Arg311Lys (R311K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). This variant, also reported as Arg297Lys using an alternate reference sequence, has been reported in individuals with ovarian, lung, breast, or colon cancers (Lu 2015, Tung 2015, Pearlman 2017). MUTYH Arg311Lys was observed at an allele frequency of 0.08% (19/24,006) in individuals of African ancestry in large population cohorts (Lek 2016). MUTYH Arg311Lys is located within the APE1 binding domain and the 9-1-1 binding domain (Parker 2001, Yang 2001, Shi 2006, Luncsford 2010). 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 Arg311Lys 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.
Ambry Genetics RCV000160757 SCV000215183 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-26 criteria provided, single submitter clinical testing The p.R311K variant (also known as c.932G>A), located in coding exon 10 of the MUTYH gene, results from a G to A substitution at nucleotide position 932. The arginine at codon 311 is replaced by lysine, an amino acid with highly similar properties. This alteration was reported in the germline of an individual with ovarian cancer from a cohort of 4034 individuals with cancer undergoing whole exome sequencing (Lu C et al. Nat. Commun. 2015 Dec;6:10086). This amino acid position is not well conserved in available vertebrate species, and lysine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000168393 SCV000219086 uncertain significance MYH-associated polyposis 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 311 of the MUTYH protein (p.Arg311Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs149342980, ExAC 0.1%). This variant has been observed in individual(s) with ovarian, breast, and colon cancers (PMID: 26689913, 25186627, 27978560). This variant is also known as c.890G>A (p.Arg297Lys). ClinVar contains an entry for this variant (Variation ID: 182694). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina RCV000168393 SCV000357897 uncertain significance MYH-associated polyposis 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000168393 SCV000487364 uncertain significance MYH-associated polyposis 2016-06-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212710 SCV000601663 uncertain significance not specified 2017-02-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212710 SCV000697715 uncertain significance not specified 2020-07-10 criteria provided, single submitter clinical testing Variant summary: MUTYH c.932G>A (p.Arg311Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 282768 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.0008 vs 0.0046), allowing no conclusion about variant significance. c.932G>A has been reported in the literature in individuals affected with different types of cancers (Tung_2015, Lu_2015, Pearlman_2016). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten other 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. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics,PreventionGenetics RCV000590230 SCV000806371 uncertain significance not provided 2017-02-20 criteria provided, single submitter clinical testing
Mendelics RCV000168393 SCV000837760 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765175 SCV000896408 uncertain significance MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000160757 SCV000910764 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-30 criteria provided, single submitter clinical testing This missense variant replaces arginine with lysine at codon 311 of the MUTYH protein. This variant is also known as NM_001048171.1:c.890G>A (p.Arg297Lys) in the literature. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant is observed in individuals affected with colon, ovarian, breast and lung cancer (PMID: 25186627, 26689913, 27978560). This variant has been identified in 36/282768 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.

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