ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1219C>T (p.His407Tyr)

gnomAD frequency: 0.00019  dbSNP: rs141432759
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129005 SCV000172901 likely benign Hereditary cancer-predisposing syndrome 2021-08-11 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.
GeneDx RCV000587968 SCV000211417 uncertain significance not provided 2023-06-15 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23108399)
Counsyl RCV000410796 SCV000487350 uncertain significance Familial adenomatous polyposis 2 2016-04-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000410796 SCV000639271 uncertain significance Familial adenomatous polyposis 2 2024-02-01 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 435 of the MUTYH protein (p.His435Tyr). This variant is present in population databases (rs141432759, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 140816). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health RCV000129005 SCV000685564 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-25 criteria provided, single submitter clinical testing This missense variant replaces histidine with tyrosine at codon 435 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 10/282744 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004525829 SCV000697665 uncertain significance not specified 2024-03-11 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1303C>T (p.His435Tyr) results in a conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251338 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Although reported as a VUS in settings of multigene panel testing for Biliary tract cancer (Okawa_2023), to our knowledge, no occurrence of c.1303C>T in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36243179). ClinVar contains an entry for this variant (Variation ID: 140816). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health RCV000410796 SCV004829208 uncertain significance Familial adenomatous polyposis 2 2024-02-05 criteria provided, single submitter clinical testing This missense variant replaces histidine with tyrosine at codon 435 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 10/282744 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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