Submissions for variant NM_001048174.2(MUTYH):c.914-9C>T

gnomAD frequency: 0.00045  dbSNP: rs3219488

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000986302	SCV000153853	likely benign	Familial adenomatous polyposis 2	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000126894	SCV000170425	benign	not specified	2014-02-10	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.
Color Diagnostics, LLC DBA Color Health	RCV000448544	SCV000537433	likely benign	Hereditary cancer-predisposing syndrome	2016-06-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000126894	SCV000697718	likely benign	not specified	2024-03-29	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.998-9C>T alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00039 in 224190 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00039 vs 0.0046), allowing no conclusion about variant significance. c.998-9C>T has been reported in the literature in individuals affected with colorectal/breast cancer (example, Aretz_2006, Kury_2007, Sulova_2007, Yurgelun_2015, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16557584, 17931073, 17524638, 25186627, 25980754). ClinVar contains an entry for this variant with a majority consensus as likely benign (Variation ID: 132703). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000590480	SCV000806372	likely benign	not provided	2017-11-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590480	SCV000889537	likely benign	not provided	2022-07-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000986302	SCV001135254	likely benign	Familial adenomatous polyposis 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590480	SCV001147266	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590480	SCV001159800	likely benign	not provided	2023-06-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000986302	SCV001255469	uncertain significance	Familial adenomatous polyposis 2	2018-10-02	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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000590480	SCV002011051	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000448544	SCV002532352	likely benign	Hereditary cancer-predisposing syndrome	2021-03-29	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000126894	SCV002552502	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000448544	SCV002688913	likely benign	Hereditary cancer-predisposing syndrome	2019-09-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
All of Us Research Program, National Institutes of Health	RCV000986302	SCV004823449	likely benign	Familial adenomatous polyposis 2	2024-02-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353610	SCV000592704	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MUTYH c.998-9C>T variant was identified in the heterozygous state in 3 of 3178 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch syndrome-associated cancer and/or polyps, or FAP/AFAP (Yurgelun 2015, Aretz 2006). The variant was also identified in dbSNP (ID: rs3219488) as “With other allele”, ClinVar (classified as benign by GeneDx; as likely benign by Invitae, Color, Prevention Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano; and as uncertain significance by Integrated Genetics/Laboratory Corporation of America). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 103 of 251118 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 22150 chromosomes (freq: 0.00005), Other in 9 of 5946 chromosomes (freq: 0.002), Latino in 20 of 31626 chromosomes (freq: 0.0006), European Non-Finnish in 62 of 112936 chromosomes (freq: 0.0005), East Asian in 10 of 17302 chromosomes (freq: 0.0006), and South Asian in 1 of 28788 chromosomes (freq: 0.00004), while not observed in the Ashkenazi Jewish or European Finnish populations. 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.