ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.841C>T (p.Arg281Cys) (rs138089183)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131155 SCV000186097 likely benign Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Other data supporting benign classification
GeneDx RCV000034682 SCV000211411 uncertain significance not provided 2018-10-26 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.925C>T at the cDNA level, p.Arg309Cys (R309C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant, also annotated as MUTYH Arg295Cys (c.883C>T) or MUTYH Arg281Cys (c.841C>T) using alternate transcripts (NM_001048174.1, NM_001048173.1), was observed in two individuals with colorectal polyps and no personal history of cancer, one of whom was also found to harbor a second MUTYH variant, and in two individuals with colorectal polyps and/or cancer (Sieber 2003, Aretz 2006, Olschwang 2007, Vogt 2009, Nielsen 2009). It has also been reported in three individuals with colorectal cancer and no polyps, one of whom was found to carry a missense variant in one of the mismatch repair genes (Halford 2003, Niessen 2006, Rohlin 2017), as well as in individuals with other cancers or polyps (Yurgelun 2015, Maxwell 2016). In a breast cancer case-control study, MUTYH Arg309Cys was identified in 7/454 (1.5%) individuals with a personal/family history suspicious for a hereditary breast cancer syndrome and 9/1,263 (0.7%) controls, but this difference was not statistically significant (p=0.15) (Out 2012). While some functional studies have shown this variant to retain normal levels of glycosylase activity in vitro, others have demonstrated significant decreases in both enzyme activity and binding affinity to damaged DNA, as well as defective base excision repair activity (Goto 2010, Brinkmeyer 2015, Komine 2015). MUTYH Arg309Cys was observed at an allele frequency of 0.09% (115/126,606) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the APE1 and 9-1-1 binding domains (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 Arg309Cys 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 RCV000198445 SCV000254716 uncertain significance MYH-associated polyposis 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 309 of the MUTYH protein (p.Arg309Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs138089183, ExAC 0.08%). This variant has been reported in individuals with adenomatous polyps and colorectal cancer (PMID: 19394335, 19732775, 19032956, 12606733, 16557584, 16408224, 12707038, 17949294, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant has also been reported in individuals with breast cancer and unaffected controls (PMID: 22297469). This variant is also known as c.883C>T (Arg295Cys) and c.841C>T (Arg281Cys) in the literature. ClinVar contains an entry for this variant (Variation ID: 41765). This variant has been reported not to substantially affect MUTYH protein function (PMID: 20848659, 26377631). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034682 SCV000601662 uncertain significance not provided 2020-03-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212709 SCV000697714 uncertain significance not specified 2021-04-02 criteria provided, single submitter clinical testing Variant summary: MUTYH c.925C>T (p.Arg309Cys) results in a non-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 0.00048 in 254474 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00048 vs 0.0046), allowing no conclusion about variant significance. c.925C>T has been reported in the literature spanning years 2003-2020 among individuals affected with APC-negative adenomatous polyposis, colorectal cancer and other tumor phenotypes without strong evidence for causality. Thus, these report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. Several publications have reported conflicting experimental evidence evaluating an impact on protein function. Multiple studies showed discordant results for adenine glycosylase activity with values similar to the wild-type enzyme (Goto_2010) while another report demonstrated low fractions of active enzyme, compromised affinity for damaged DNA and reduced rates for adeninine excision (Brinkmeyer_2015). The variant did not affect binding of MUTYH with the Hus1 subunit of the 9-1-1 heterotrimeric complex, Rad9-Hus1-Rad1, which is thought to stimulate the glycosylase activity of the protein (Brinkmeyer_2015). Lastly, a complementation assay evaluating the functional deficiency in the E Coli by monitoring spontaneous mutation rates showed a partially defective activity (Komine_2015). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments namely VUS (n=8), likely benign (n=1) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics,PreventionGenetics RCV000034682 SCV000806370 uncertain significance not provided 2017-12-21 criteria provided, single submitter clinical testing
GeneKor MSA RCV000131155 SCV000822081 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000198445 SCV000837761 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000034682 SCV000859723 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131155 SCV000910575 benign Hereditary cancer-predisposing syndrome 2016-06-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000198445 SCV001255471 uncertain significance MYH-associated polyposis 2018-03-08 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034682 SCV000043374 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000198445 SCV001553145 uncertain significance MYH-associated polyposis no assertion criteria provided clinical testing The MUTYH p.Arg309Cys variant was identified in 11 of 6552 proband chromosomes (frequency: 0.002) from individuals or families with MAP, colorectal cancer, or breast cancer and was present in 9 of 3332 control chromosomes (frequency: 0.003) from healthy individuals (Aretz 2006, Halford 2003, Jones 2009, Nielsen 2009, Olschwang 2007, Out 2012, Rohlin 2017, Sieber 2003, Vogt 2009). Note that the variant was identified as c.883C>T (NM_001048171.1), p.Arg295Cys (NP_001041636.1) and p.Arg281Cys (NP_001041638.1) in the literature (Goto 2010, Komine 2015, Brinkmeyer 2015). The variant was also identified in dbSNP (ID: rs138089183) as "With Uncertain significance allele", and in ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by GeneDx, Invitae, and three clinical laboratories). The variant was not identified in COGR, Cosmic, or the UMD-LSDB database. The variant was identified in control databases in 129 of 277082 chromosomes at a frequency of 0.0005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24006 chromosomes (freq: 0.00004), Other in 5 of 6466 chromosomes (freq: 0.0008), Latino in 4 of 34414 chromosomes (freq: 0.0001), European in 115 of 126606 chromosomes (freq: 0.0009), Finnish in 3 of 25792 chromosomes (freq: 0.0001), and South Asian in 1 of 30780 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish, or East Asian populations. The p.Arg309 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 occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant exhibited low levels of active enzyme (5%) compared to WT MUTYH and displayed a significant decrease in substrate binding affinity relative to the WT enzyme (Brinkmeyer 2015). In addition, in an in vitro glycosylase assay two studies displayed the variant having normal glycosylase activity (Goto 2010, Komine 2015) but a third showed that glycosylase activity was less efficient (Brinkmeyer 2015). 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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