Submissions for variant NM_001048174.2(MUTYH):c.1501C>A (p.Leu501Met)

gnomAD frequency: 0.00154  dbSNP: rs3219496

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034673	SCV000149671	likely benign	not provided	2021-07-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 21167187, 25820570, 22703879, 21153778, 28944238)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000986299	SCV000166450	benign	Familial adenomatous polyposis 2	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115762	SCV000187514	benign	Hereditary cancer-predisposing syndrome	2018-11-07	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Vantari Genetics	RCV000115762	SCV000267058	benign	Hereditary cancer-predisposing syndrome	2016-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115762	SCV000685598	benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	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	2022-08-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000986299	SCV001135247	likely benign	Familial adenomatous polyposis 2	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 Laboratory Services, Illumina	RCV000986299	SCV001257600	likely benign	Familial adenomatous polyposis 2	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.
Fulgent Genetics, Fulgent Genetics	RCV002490462	SCV002803524	likely benign	Familial adenomatous polyposis 2; Gastric cancer	2021-11-11	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115762	SCV005205773	benign	Hereditary cancer-predisposing syndrome	2024-07-09	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000034673	SCV005262068	likely benign	not provided		criteria provided, single submitter	not provided
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