ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.925C>T (p.Arg309Cys) (rs138089183)

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Total submissions: 11
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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 2017-08-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign) ,Other data supporting benign classification
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.
Color RCV000131155 SCV000910575 benign Hereditary cancer-predisposing syndrome 2016-06-22 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
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.
GeneKor MSA RCV000131155 SCV000822081 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000034682 SCV000697714 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The c.925C>T (p.Arg309Cys) in MUTYH gene is a missense change that involves a non- conserved nucleotide and 5/5 in silico tools predict benign outcome. The R309C variation is located in the IDC region of MUTYH and several functional studies showed discordant results for adenine glycosylase reactions depending on salt concentration (Goto, 2010; Komine, 2015; Brinkmeyer, 2015). R309 exhibited low level of active enzyme, but did not affect the interactions between MUTYH and Hus1 (Brinkmeyer, 2015). The variant is present in the control population dataset of ExAC at frequency of 0.0004378 (53/ 121072 chrs tested), predominantly in individuals of European descent (0.0008; 51/ 66504 chrs tested). The observed frequencies do not exceed the maximum expected allele frequency for a pathogenic variant of 0.0046. The c.925C>T has been reported heterozygously in multiple FAP/AFAP, CRC and BrC cases without strong evidence for causality. In addition, c.925C>T was identified homozygously in early onset CRC without polyps with normal IHC staining for MMR proteins (Rohlin, 2017). Based on the clinical presentation of the carriers and results of the functional studies, c.925C>T may represent a defective allele, however, more data needed to interpret the variant with confidence. Lastly, the variant is listed as VUS/Likely Benign by several reputable databases/clinical laboratories. Taking together, the variant was classified as VUS until more information becomes available.
Invitae RCV000198445 SCV000254716 uncertain significance MYH-associated polyposis 2018-12-27 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 polyposis and colorectal cancer (PMID: 19394335, 19732775, 19032956, 12606733, 16557584, 16408224, 12707038, 17949294), as well as individuals with breast cancer and unaffected control individuals (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). Experimental studies have shown that this variant has a weak to neutral effect on protein expression, glycosylase activity, and substrate affinity (PMID: 25820570, 20848659, 26377631). The clinical relevance of these results is uncertain at this time. 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.
Mendelics RCV000198445 SCV000837761 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000034682 SCV000806370 uncertain significance not provided 2017-12-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212709 SCV000601662 uncertain significance not specified 2017-03-07 criteria provided, single submitter clinical testing

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