ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1258C>A (p.Leu420Met) (rs144079536)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115755 SCV000187241 benign Hereditary cancer-predisposing syndrome 2014-06-30 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034669 SCV000043369 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CSER_CC_NCGL; University of Washington Medical Center RCV000123143 SCV000503542 uncertain significance MYH-associated polyposis 2016-08-01 no assertion criteria provided research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 36 year old with a history of 2 colon polyps and a family history of colon cancer.
Color RCV000115755 SCV000910570 benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212714 SCV000592714 likely benign not specified 2015-03-18 criteria provided, single submitter clinical testing
GeneDx RCV000034669 SCV000149664 uncertain significance not provided 2018-08-22 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1258C>A at the cDNA level, p.Leu420Met (L420M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). This variant, also denoted c.1216C>A (p.Leu406Met) and c.1249C>A (p.Leu417Met) using alternate reference sequences (NP_001041636.1 and NP_036354.1, respectively), has been observed in an individual from an HNPCC/HNPCC-like family, in multiple individuals with colorectal adenomas, and in individuals with pancreatic cancer, sarcoma, and breast cancer (Peterlongo 2006, Olschwang 2007, Smith 2009, Guarinos 2014, Ballinger 2016, Jalkh 2017, Ricci 2017, Scarpa 2017). It was also observed in 1/548 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). Komine et al. (2015) demonstrated that MUTYH Leu420Met showed spontaneous mutation rates similar to wild type in an E. coli-based complementation assay. MUTYH Leu420Met was observed at an allele frequency of 0.20% (20/10,150 alleles) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located within the NUDIX domain (Ruggieri 2013). In silico analysis, which includes protein predictors?and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MUTYH Leu420Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000115755 SCV000679735 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000034669 SCV000697673 uncertain significance not provided 2016-09-26 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.1258C>A (p.Leu420Met) variant located in the NUDIX hydrolase domain (via InterPro) causes a missense change involving a conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome for this variant. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 71/120676 (1/1699), which does not exceed the estimated maximal expected allele frequency for a pathogenic MUTYH variant of 1/219. Multiple publications have cited the variant in affected individuals, although with limited information (ie, lack of co-occurrence and cosegregation data). A functional study, Komine_2015, indicates the variant to act comparable to wild type function. Multiple clinical diagnostic laboratories cite the variant as "uncertain significance." Therefore, until addtional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000123143 SCV000166446 likely benign MYH-associated polyposis 2018-01-09 criteria provided, single submitter clinical testing
Mendelics RCV000123143 SCV000837750 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000034669 SCV000806340 uncertain significance not provided 2017-03-09 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115755 SCV000788061 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-30 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000123143 SCV000886461 likely benign MYH-associated polyposis 2018-05-17 criteria provided, single submitter research The MUTYH variant designated as NM_001128425.1:c.1258C>A (p.Leu420Met, historically known as p.Leu417Met) was previously classified as a variant of uncertain significance and is now classified as likely benign. This variant has been reported in several population databases. It is present in approximately 1 in 900 individuals with European ancestry. This population frequency is not consistent with the frequency of pathogenic mutations in MUTYH. This variant is a missense variant and pathogenic variants in MUTYH are most frequently truncating variants. This variant has been classified as likely benign and benign by other laboratories (ClinVar Variation ID: 41752). Together, this information is consistent with a likely benign variant in MUTYH. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MUTYH function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Vantari Genetics RCV000115755 SCV000267060 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-25 criteria provided, single submitter clinical testing

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