ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.956-9C>T (rs3219488)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000986302 SCV000153853 likely benign MYH-associated polyposis 2020-12-04 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 Health, Inc 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 2021-07-12 criteria provided, single submitter clinical testing Variant summary: MUTYH c.998-9C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational 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 expected 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. Eight 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 (likely benign, n=6; VUS, n=2). We have not ascertained any actionable evidence in over 4 years since its initial evaluation at our laboratory. Based on the evidence outlined above and the emerging consensus, the variant was re-classified as likely benign.
PreventionGenetics,PreventionGenetics 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 2020-01-03 criteria provided, single submitter clinical testing
Mendelics RCV000986302 SCV001135254 likely benign MYH-associated polyposis 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590480 SCV001147266 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000126894 SCV001159800 likely benign not specified 2018-10-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000986302 SCV001255469 uncertain significance MYH-associated polyposis 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.
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.

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