ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.566G>A (p.Arg189His) (rs147754007)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129023 SCV000172924 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-02 criteria provided, single submitter clinical testing <span style="background-color:initial">The p.R217H<span style="background-color:initial"> variant (also known as c.650G>A), located in coding exon 8 of the MUTYH<span style="background-color:initial"> gene, results from a G to A substitution at nucleotide position 650. The arginine at codon 217 is replaced by histidine, an amino acid with highly similar properties. This alteration, designated as p.Arg203His, has been reported as a variant of unknown significance in an adenomatous polyposis cohort (Olschwang S et al. Genet. Test.<span style="background-color:initial"> 2007;11:315-20). In a different study, this alteration was detected in a large Austrian kindred with familial colorectal cancer type <span style="background-color:initial">X (FCCTX) in conjunction with a SEMA4A gene alteration; this alteration did not segregate with colorectal cancer in the family whereas the SEMA4A gene alteration did (Schulz E et al. Nat Commun. 2014 Oct 13;5:5191<span style="background-color:initial">). In addition, this alteration was detected in the germline of an individual with advanced cancer who underwent tumor-normal sequencing; although clinical details were not provided, authors noted that the patient's phenotypic expression was not consistent with an autosomal recessive mode of inheritance (Schrader KA et al. JAMA Oncol. 2016 Jan;2(1):104-11<span style="background-color:initial">). 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.​
Counsyl RCV000411202 SCV000487316 uncertain significance MYH-associated polyposis 2015-12-08 criteria provided, single submitter clinical testing
Invitae RCV000411202 SCV000545748 uncertain significance MYH-associated polyposis 2020-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 217 of the MUTYH protein (p.Arg217His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs147754007, ExAC 0.009%). This variant has been reported in an individual affected with colorectal cancer (PMID: 17949294). This variant has also been reported in a family with familial colorectal cancer, but it did not segregate with disease while a variant in a different gene that segregated with disease was identified (PMID: 25307848). This variant is also known as c.608G>A (p.Arg203His) in the literature. ClinVar contains an entry for this variant (Variation ID: 140830). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
GeneDx RCV000766702 SCV000570801 uncertain significance not provided 2019-01-03 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.650G>A at the cDNA level, p.Arg217His (R217H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant, also published as MUTYH 608G>A using alternate nomenclature, has been observed in the heterozygous state in individuals with colorectal adenomas, as well as in individuals with colorectal, breast, and prostate cancers (Olschwang 2007, Schulz 2014). Although this heterozygous MUTYH variant was identified by whole-exome sequencing in two individuals with colorectal cancer from one family with familial colorectal cancer, no other MUTYH variants were identified in these individuals and MUTYH Arg217His was not found to co-segregate with all colorectal cancer and colorectal adenomas in this family (Schulz 2014). MUTYH Arg217His was observed at an allele frequency of 0.01% (3/23,996) 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 a deleterious effect. Based on currently available evidence, it is unclear whether MUTYH Arg217His 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.
Color Health, Inc RCV000129023 SCV000685654 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-04 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 217 of the MUTYH protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal adenomas (PMID 17949294), in a family with familial colorectal cancer; however, the variant did not segregate with the disease (PMID 25307848) and in an individual(s) with unspecified cancer (PMID: 26556299). This variant has been identified in 11/282760 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.
Mendelics RCV000411202 SCV000837768 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000482890 SCV000592690 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Arg217His variant was identified in APC-negative patients with more than 5 colorectal adenomas; the frequency of the variant in this cohort, zygosity and disease severity were not provided from this cohort (Olschwang 2007). It was also identified in a large Austrian kindred with Familial colorectal cancer type X (FCCTX), being studied for novel candidate gene mutations; but was excluded as the cause of neoplasms in this family due to non-segregation amongst family members (Schulz 2014). The variant was also identified in dbSNP (ID: rs147754007) as “With Uncertain significance allele”, Clinvitae database (classification uncertain significance), ClinVar database (classification uncertain significance by Ambry Genetics), UMD (2x with a ”unclassified variant” classification), NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles (frequency: 0.0001) and in 1 of 4406 African American alleles (frequency: 0.0002), and the Exome Aggregation Consortium database (March 14, 2016) in 5 of 121252 chromosomes (freq. 0.00004) in the following populations: Latino in 1 of 11572 chromosomes (freq. 00009), South Asian in 1 of 16512 chromosomes (freq. 0.00006), European (Non-Finnish) in 3 of 66638 chromosomes (freq. 0.00005), but was not seen in African, East Asian, Finnish, and Other populations, increasing the likelihood this could be a low frequency benign variant. The p.Arg217 residue is conserved across mammals and lower organisms, and three out of four computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the His variant may impact the protein; however, this information is not predictive enough to assume 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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