ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.254A>G (p.His85Arg) (rs558707786)

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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 RCV000220679 SCV000278483 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-23 criteria provided, single submitter clinical testing The p.H85R variant (also known as c.254A>G), located in coding exon 3 of the MUTYH gene, results from an A to G substitution at nucleotide position 254. The histidine at codon 85 is replaced by arginine, an amino acid with highly similar properties. This alteration was reported in the homozygous state in a Turkish individual with 10-100 polyps at age 50 and a sister with colorectal cancer at age 55; the authors noted that this alteration is not in a functional domain and is not predicted to affect splicing, and classified this alteration as a variant of unknown significance (Morak M et al. Clin. Genet. 2010 Oct; 78(4):353-63). 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 RCV000505782 SCV000322182 likely pathogenic not provided 2016-11-30 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.254A>G at the cDNA level, p.His85Arg (H85R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant was observed in the homozygous state in a patient who had a history of 10-100 colorectal adenomas and a sibling with colorectal cancer (Morak 2010). MUTYH His85Arg was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. MUTYH His85Arg occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence and internal data, we consider MUTYH His85Arg to be a likely pathogenic variant. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.
Color Health, Inc RCV000220679 SCV001344063 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-06 criteria provided, single submitter clinical testing
Invitae RCV001219416 SCV001391352 uncertain significance MYH-associated polyposis 2020-09-30 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 85 of the MUTYH protein (p.His85Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs558707786, ExAC 0.01%). This variant has been observed in an individual with clinical features of adenomatous polyposis (between 10-100 polyps) (PMID: 20618354). ClinVar contains an entry for this variant (Variation ID: 234004). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420901 SCV001623340 uncertain significance not specified 2021-04-16 criteria provided, single submitter clinical testing Variant summary: MUTYH c.254A>G (p.His85Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251476 control chromosomes. c.254A>G has been reported in the literature in one homozygous individual affected with 10-100 colorectal adenomas and a sibling affected with colorectal cancer (Morak_2010). Additionally, the variant was also reported in one individual with MUTYH-Associated Polyposis (Sutcliffe_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354525 SCV001549166 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.His85Arg variant was not identified in the literature nor was it identified in the following databases: Cosmic, MutDB, Insight Colon Cancer Gene Variant Database. The variant was identified in dbSNP (ID: rs558707786) as “With Uncertain significance allele”,ClinVar (1x as uncertain significance by Ambry Genetics), and Clinvitae (1x as uncertain significance). The variant was identified in control databases in 2 of 246258 chromosomes at a frequency of 0.000008 in the following populations: African in 1 of 15304 chromosomes (freq. 0.000065), and Other in 1 of 5486 chromosomes (freq. 0.00018) (Genome Aggregation Consortium Feb 27, 2017). The p.His85Arg 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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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