ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1187G>A (p.Gly396Asp) (rs36053993)

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Total submissions: 33
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000121598 SCV000604306 pathogenic not specified 2017-06-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115748 SCV000184573 pathogenic Hereditary cancer-predisposing syndrome 2018-04-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function by in vitro/ex vivo assay,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Other strong data supporting pathogenic classification
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000005614 SCV000043370 pathogenic MYH-associated polyposis 2012-07-13 no assertion criteria provided research Converted during submission to Pathogenic.
Center for Human Genetics, Inc RCV000005614 SCV000781800 pathogenic MYH-associated polyposis 2016-11-01 criteria provided, single submitter clinical testing
Color RCV000115748 SCV000537630 pathogenic Hereditary cancer-predisposing syndrome 2016-02-16 criteria provided, single submitter clinical testing
Counsyl RCV000005614 SCV000678192 pathogenic MYH-associated polyposis 2015-07-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000005614 SCV000592711 pathogenic MYH-associated polyposis 2016-11-09 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477907 SCV000536693 pathogenic MYH-associated polyposis; Neoplasm of stomach 2015-06-04 no assertion criteria provided research
Donald Williams Parsons Laboratory,Baylor College of Medicine RCV000005614 SCV000599972 pathogenic MYH-associated polyposis 2015-10-12 no assertion criteria provided research This variant has been previously reported as disease-causing. It would be pathogenic in a recessive state; heterozygotes would be carriers for the condition. It was found once in our study heterozygous in a 6-year-old male with anaplastic ganglioglioma.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079501 SCV000111383 pathogenic not provided 2018-02-27 criteria provided, single submitter clinical testing
Endocrine oncology group,Uppsala University RCV000493920 SCV000536689 likely pathogenic Small intestine carcinoid 2017-03-09 no assertion criteria provided case-control
Fulgent Genetics,Fulgent Genetics RCV000515320 SCV000611285 pathogenic MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000079501 SCV000149657 pathogenic not provided 2018-10-29 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.1187G>A at the cDNA level, p.Gly396Asp (G396D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). MUTYH Gly396Asp, also annotated as Gly382Asp using a different gene transcript, is one of two common MUTYH pathogenic variants which together account for up to 80% of pathogenic MUTYH variants. It has been observed in the homozygous and compound heterozygous state in multiple individuals with MUTYH-Associated Polyposis, including affected siblings (Al-Tassan 2002, de Leon 2017, Yurgelun 2017). Multiple in vitro functional studies demonstrate this variant's pathogenic effect (Al-Tassan 2002, Ali 2008, Goto 2010). MUTYH Gly396Asp was observed at an allele frequency of 0.48% (611/126146) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the 8-oxo-G binding site within the Nudix domain (Ruggieri 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. We consider this variant to be pathogenic.
GeneKor MSA RCV000115748 SCV000821744 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
GeneReviews RCV000005614 SCV000057867 pathogenic MYH-associated polyposis 2015-09-24 no assertion criteria provided literature only
Genetic Services Laboratory, University of Chicago RCV000501239 SCV000595873 pathogenic Colorectal adenomatous polyposis, autosomal recessive, with pilomatricomas 2016-08-26 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000586537 SCV000840099 not provided MUTYH-associated polyposis no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000005614 SCV000993433 likely pathogenic MYH-associated polyposis 2019-01-22 criteria provided, single submitter research
ITMI RCV000121598 SCV000085795 not provided not specified 2013-09-19 no assertion provided reference population
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000115748 SCV000679736 pathogenic Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586537 SCV000697670 pathogenic MUTYH-associated polyposis 2017-08-09 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.1187G>A (p.Gly396Asp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant. Functional studies support a damaging outcome, and at least 2 independent labs have down reduced DNA glycosylase activity and a reduced ability to suppress the mutation frequency in a complementation assay. This variant was found in 339/120440 control chromosomes (2 homozygotes) at a frequency of 0.0028147, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). The variant has been reported in numerous patients in the literature, and is known as a common pathogenic variant. In addition, many clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000005614 SCV000166443 pathogenic MYH-associated polyposis 2019-01-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 396 of the MUTYH protein (p.Gly396Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is a known common cause of MUTYH-associated polyposis (PMID: 23035301). This variant has been reported to co-segregate with disease in individuals affected with colorectal cancer, familial adenomatous polyposis (FAP), and attenuated FAP (PMID: 11818965, 16557584, 17489848, 19793053). This variant is also known as c.1145G>A (p.Gly382Asp) in the literature. ClinVar contains an entry for this variant (Variation ID: 5294). MUTYH-related conditions are inherited in an autosomal recessive fashion. However, there is evidence that monoallelic pathogenic MUTYH variants including this particular variant are associated with increased risk of colon cancer (PMID: 16492921, 19394335, 21171015, 24444654, 15931596). Experimental studies have shown that this missense change disrupts MUTYH protein function (PMID: 15987719, 18534194, 20848659, 23108399). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000005614 SCV000245638 pathogenic MYH-associated polyposis 2015-03-04 criteria provided, single submitter clinical testing The p.Gly396Asp variant in MUTYH is a well-established pathogenic variant for MU TYH-related attenuated familial adenomatous polyposis and is estimated to accoun t for 50-82% of MUTYH-associated polyposis in European patients (Al-Tassan 2002, Nielsen 2009, Vogt 2009, Nascimbeni 2010, Aretz 2014, ClinVar: Variation ID 529 4). In vitro functional studies provide some evidence that the p.Gly396Asp varia nt may impact protein function (Al-Tassan 2002, Ali 2008, Goto 2010). This vari ant has also been identified in 0.5% (608/126146) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP r s36053993); however, this frequency is low enough to be consistent with a recess ive carrier frequency. Computational prediction tools and conservation analysis suggest that the p.Gly396Asp variant may impact the protein. In summary, this va riant meets criteria to be classified as pathogenic for MUTYH-associated polypos is in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PS3_Supporting.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000079501 SCV000691947 pathogenic not provided no assertion criteria provided clinical testing
Mendelics RCV000005614 SCV000837751 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
OMIM RCV000005614 SCV000025796 pathogenic MYH-associated polyposis 2011-09-01 no assertion criteria provided literature only
OMIM RCV000005615 SCV000025797 pathogenic endometrial cancer 2011-09-01 no assertion criteria provided literature only
Pathway Genomics RCV000144637 SCV000189964 pathogenic Carcinoma of colon 2014-07-24 no assertion criteria provided clinical testing
PreventionGenetics RCV000079501 SCV000806339 pathogenic not provided 2016-03-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000079501 SCV000601628 pathogenic not provided 2016-08-15 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115748 SCV000788060 pathogenic Hereditary cancer-predisposing syndrome 2017-12-29 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000115748 SCV000266099 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Vantari Genetics RCV000115748 SCV000267061 pathogenic Hereditary cancer-predisposing syndrome 2015-12-21 criteria provided, single submitter clinical testing

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