ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1192C>T (p.Arg398Cys) (rs150792276)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212715 SCV000149665 uncertain significance not specified 2017-06-06 criteria provided, single submitter clinical testing MUTYH Arg426Cys, previously reported as c.1234C>T and Arg412Cys using alternate nomenclature, has been observed in the heterozygous state in several individuals with adenomatous polyps, one of whom had more than 100 adenomas, with none reported to have a second MUTYH pathogenic variant (Aceto 2005, Aretz 2006, Sulova 2007, de Leon 2013). It was also observed in 1/257 individuals with lung cancer, and 1/572 individual with atherosclerosis with no specific information about cancer history (Fleischmann 2004, Johnston 2012). Functional analysis using a yeast complementation assay revealed MUTYH Arg426Cys to have base excision repair activity similar to wild-type (Komine 2015). MUTYH Arg426Cys was observed with an allele frequency of 0.1% (8/8600) in European Americans in the NHLBI Exome Sequencing Project. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MUTYH Arg426Cys occurs at a position that is not conserved and is located within the Nudix domain (Ruggieri 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MUTYH Arg426Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000119122 SCV000153836 likely benign MYH-associated polyposis 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115756 SCV000172769 likely benign Hereditary cancer-predisposing syndrome 2019-04-27 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Intact protein function observed by in vitro/ex vivo assays;Sub-population frequency in support of benign classification (not ava blue, manual h-w)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034670 SCV000601632 uncertain significance not provided 2020-03-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212715 SCV000697674 uncertain significance not specified 2021-05-03 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1276C>T (p.Arg426Cys) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of 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 0.00082 in 397754 control chromosomes, predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database (v2.1 and v3.1 datasets), including 2 homozygotes. This frequency is not higher than the maximum expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.0046), allowing no conclusion about variant significance. c.1276C>T has been reported in multiple FAP or attenuated FAP patients in monoallelic state (e.g. Aceto_2005, Aretz_2006, de Lyon_2013, Ricci_2017, Sulova_2009). Furthermore, it has been reported with other pathogenic MUTYH variants in biallelic patients affected with synchronous/metachronous polyps (Lopez-Villar_2010) and colorectal cancer (e.g. De Rycke 2017, Yurgelun 2017). Additional reports of the variant in individuals with a personal and/or family history of colorectal cancer, HBOC, lung and endometrial cancer have also been published (e.g. Fleischmann_2004, Ricci_2016, Ring_2016, Tung_2016, Martin-Morales_2018, Rizzolo_2018, Oliver_2019, Lin_2019, Tsaousis_2019, Grasel_2020, Pope_2021). These data do not allow clear conclusions about variant significance. One functional study showed that the variant had comparable function to wild-type in terms of suppression of spontaneous mutations (Komine_2015). Co-occurrences with pathogenic variants have been reported (BRCA2 c.4647_4650delAGAG, p.Lys1549fsX18; APC c.2161_2170delGGAAGTGCTG, p.Gly721fsX3; MSH6 c.3013C>T, p.Arg1005X; PALB2 c.2386G>T, p.Gly796X; Internal testing). 12 other 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, i.e. likely benign (n=4) and uncertain significance (n=8). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212715 SCV000711723 uncertain significance not specified 2017-01-11 criteria provided, single submitter clinical testing The p.Arg426Cys variant in MUTYH has been reported in at > 8 individuals with co lorectal cancer (Aceto 2005, Aretz 2006, Sulova 2007, Gomez-Fernadez 2009, Lopez -Villar 2010, Guarinos 2014, Yurgelun 2015, Ricci 2017), 2 individuals with brea st cancer (Tung 2016), 1 individual with lung cancer (Al-Tassan 2004) and has a lso been reported by other clinical laboratories in ClinVar (Variation ID 41753) . All individuals reported in the literature were heterozygous and did not carry a second MUTYH variant. This variant has also been identified in 0.1% (184/1266 06) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Althou gh this variant has been seen in the general population, its frequency is not hi gh enough to rule out a pathogenic role. In vitro functional studies provide som e evidence that the p.Arg426Cys variant may not impact protein function (Komine 2015) and computational prediction tools and conservation analysis suggest that the p.Arg426Cys variant may not impact the protein, though this information is n ot predictive enough to rule out pathogenicity. In summary, the clinical signifi cance of the p.Arg426Cys variant is uncertain. ACMG/AMP Criteria applied: BP4.
PreventionGenetics,PreventionGenetics RCV000034670 SCV000806341 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115756 SCV000822073 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000119122 SCV000837748 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000212715 SCV000885747 likely benign not specified 2018-08-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115756 SCV000902581 likely benign Hereditary cancer-predisposing syndrome 2016-11-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000119122 SCV001253576 uncertain significance MYH-associated polyposis 2017-04-27 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled 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 RCV000034670 SCV000043368 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Pathway Genomics RCV000144640 SCV000189967 uncertain significance Carcinoma of colon 2014-07-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000144640 SCV000592715 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Arg426Cys variant was identified in 15 of 6049 proband chromosomes (frequency: 0.003) from individuals or families with FAP, MAP, early onset colorectal cancer or breast cancer and was present in 1 of 1152 control chromosomes (frequency: 0.001) from healthy individuals (Lopez-Villar 2010, Fleischmann 2004, Aceto 2005, Aretz 2006, Kanter-Smoler 2006, Guarinos 2014, DeRycke 2017, Ricci 2017, Tung 2016). In functional complementation tests using E. coli and monitoring spontaneous mutation rates, the variant was found to be functionally retained (Komine 2015). The variant was also identified in dbSNP (ID: rs150792276) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and Ambry Genetics; as uncertain significance by GeneDx and nine other submitters) and in UMD (8x as an unvalidated variant). In UMD the variant was identified with co-occurring pathogenic MUTYH variants c.1145G>A, p.Gly382Asp and c.692G>A, p.Arg231His. The variant was also identified by our laboratory in 5 individuals with colon cancer (no co-occurrence with a pathogenic variant). The variant was identified in control databases in 226 of 277022 chromosomes (1 homozygous) at a frequency of 0.0008 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 8 of 24010 chromosomes (freq: 0.0003), Other in 7 of 6454 chromosomes (freq: 0.001), Latino in 8 of 34418 chromosomes (freq: 0.0002), European in 184 of 126606 chromosomes (freq: 0.001), East Asian in 19 of 18866 chromosomes (freq: 0.001); it was not observed in the Ashkenazi Jewish, Finnish, and South Asian populations. The p.Arg426 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.
True Health Diagnostics RCV000115756 SCV000788062 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-28 no assertion criteria provided clinical testing

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