ClinVar Miner

Submissions for variant NM_012222.2(MUTYH):c.1576C>A (p.Leu526Met) (rs3219496)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000121603 SCV000149671 likely benign not specified 2018-01-22 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000986299 SCV000166450 benign MYH-associated polyposis 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115762 SCV000187514 benign Hereditary cancer-predisposing syndrome 2018-11-07 criteria provided, single submitter clinical testing General population or sub-population frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign) ;Other data supporting benign classification;Sub-population frequency in support of benign classification (not ava blue, manual h-w)
Vantari Genetics RCV000115762 SCV000267058 benign Hereditary cancer-predisposing syndrome 2016-01-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121603 SCV000601640 likely benign not specified 2017-07-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115762 SCV000685598 benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121603 SCV000806349 benign not specified 2016-12-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034673 SCV000889529 benign not provided 2018-07-31 criteria provided, single submitter clinical testing
Mendelics RCV000986299 SCV001135247 likely benign MYH-associated polyposis 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000121603 SCV001157130 benign not specified 2018-09-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000986299 SCV001257600 likely benign MYH-associated polyposis 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034673 SCV000043365 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000121603 SCV000085800 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144641 SCV000189968 likely benign Carcinoma of colon 2014-12-15 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000144641 SCV000592722 benign Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Leu529Met variant was identified in the literature, although the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (rs3219496) as “with other allele”, ClinVar (classified as likely benign by Ambry Genetics, GeneDx, Pathway Genomics and 3 other submitters; and as benign by Invitae, Color, PreventionGenetics and 2 other submitters). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 893 of 282,882 chromosomes (16 homozygous) at a frequency of 0.003, 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: Latino in 852 of 35,440 chromosomes (freq: 0.02), Other in 16 of 7226 chromosomes (freq: 0.002), African in 15 of 24,966 chromosomes (freq: 0.0006), East Asian in 3 of 19,954 chromosomes (freq: 0.0002), European in 6 of 129,186 chromosomes (freq: 0.00005), and South Asian in 1 of 30,616 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish or Finnish populations. Site-directed mutagenesis experiments demonstrated that the variant did not alter the functional activity of MUTYH in E. coli cells (Komine 2015). The p.Leu529 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 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, this variant meets our laboratory's criteria to be classified as benign.
True Health Diagnostics RCV000115762 SCV000788067 likely benign Hereditary cancer-predisposing syndrome 2018-02-28 no assertion criteria provided clinical testing

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