ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1103G>A (p.Gly368Asp) (rs36053993)

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Total submissions: 46
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079501 SCV000111383 pathogenic not provided 2018-02-27 criteria provided, single submitter clinical testing
GeneDx RCV000079501 SCV000149657 pathogenic not provided 2020-05-05 criteria provided, single submitter clinical testing Observed in the homozygous and compound heterozygous state in multiple individuals with MUTYH-Associated Polyposis, including affected siblings (Al-Tassan 2002, Win 2016, de Leon 2017, Furlan 2017, Yurgelun 2017); Published functional studies demonstrate a damaging effect: reduced glycosylase and DNA binding activity (Ali 2008, Goto 2010, Ruggieri 2013, Komine 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20687945, 21063410, 21952991, 22926731, 21178863, 20418187, 23361220, 28195393, 11818965, 29330641, 30564557, 32231684, 30582135, 18534194, 23108399, 20848659, 22703879, 19836313, 22744763, 19998059, 19732775, 19032956, 19953527, 22473953, 23625202, 23805267, 24082139, 22158503, 19245865, 27014339, 27194394, 26202870, 27631816, 27696107, 27705013, 27313931, 28135145, 27829682, 17039270, 24728327, 28127763, 27783336, 28141798, 27870730, 25820570, 27153395, 26332594, 26822237, 26681312, 28687356, 28944238, 28503720, 25186627, 28577310, 29371908, 29766397, 28634180, 29785153, 28152038, 26556299, 29915346, 29406563, 29958926, 30067863, 30333958, 30609409, 30256826, 30702970, 30620386, 29978187, 30322717, 30309722, 30604180, 30833417, 31159747, 30676620, 31285513, 30877237, 31512090, 30306255, 32088803, 30291343, 28709830, 31618753, 31447099, 31263571, 32854451, 31980526, 33384714, 32338768, 33258288, 32830346, 33504652)
Invitae RCV000005614 SCV000166443 pathogenic MYH-associated polyposis 2020-11-02 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 present in population databases (rs36053993, ExAC 0.4%). 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 and polyposis (with polyp numbers ranging from 10 to >100) (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.
Ambry Genetics RCV000115748 SCV000184573 pathogenic Hereditary cancer-predisposing syndrome 2019-07-31 criteria provided, single submitter clinical testing The p.G396D pathogenic mutation (also known as c.1187G>A) is located in coding exon 13 of the MUTYH gene. This alteration is a well-characterized founder mutation in multiple populations and accounts for a significant proportion of pathogenic MUTYH mutations reported to date (Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6). A large scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants, including more than 20000 cases and 15000 controls, demonstrated no significant monoallelic effects on colorectal cancer risk associated with this mutation (Theodoratou E et al. Br. J. Cancer. 2010 Dec;103:1875-84). In a cohort of 389 Sephardic Jewish women with breast cancer and 541 healthy controls, p.G396D was associated with a 1.86 fold increased risk for breast cancer (Rennert G et al. Cancer. 2012 Apr;118:1989-93). Additionally, this alteration was found to occur with an odds ratio of 2.0 in Dutch women with familial breast cancer compared to women with sporadic breast cancer and healthy controls, although this result did not reach statistical significance (Out AA et al. Breast Cancer Res.Treat. 2012 Jul;134:219-27). Functional analyses of this alteration indicate that p.G396D results in significantly reduced oxidative DNA mismatch repair efficiency compared to wild type (Plotz G et al. Hum. Mutat. 2012 Jul;33:1067-74; Raetz AG et al. Carcinogenesis. 2012 Nov;33:2301-9; Ruggieri V et al. Oncogene. 2013 Sep;32:4500-8). RNA studies have demonstrated this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). Of note, this alteration is also designated as p.G382D in the published literature. Based on the available evidence, this alteration is classified as a disease-causing mutation.
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.
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
Color Health, Inc RCV000115748 SCV000537630 pathogenic Hereditary cancer-predisposing syndrome 2021-02-11 criteria provided, single submitter clinical testing This missense variant replaces glycine with aspartic acid at codon 396 of the MUTYH protein. This variant is also known as p.Gly382Asp (c.1145G>A) based on an alternate transcript NM_001048171. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies have shown that the mutant protein to exhibit significantly reduced activity in in vitro DNA glycosylase activity assay (PMID: 15036665, 15987719, 20848659). This variant is a well-established pathogenic variant known to cause adenomatous polyposis and colorectal cancer in homozygous or compound heterozygous individuals (PMID: 11818965, 12606733, 15635083, 16557584, 23361220, 25590978, 27783336, 28135145, 29147111). This variant is one of two most common pathogenic MUTYH variants, which together account for up to 80% of MUTYH-associated disease observed in Caucasian individuals (PMID: 29147111). This variant has been identified in 860/281146 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000079501 SCV000601628 pathogenic not provided 2016-08-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282788 SCV000604306 pathogenic none provided 2019-11-03 criteria provided, single submitter clinical testing The MUTYH c.1187G>A; p.Gly396Asp variant (rs36053993; also known as NM_001048171.1: c.1145G>A; p.Gly382Asp) has been well described in the literature as one of the two common MUTYH pathogenic variants. It has been observed in homozygous or compound heterozygous form with other pathogenic MUTYH variants in patients with adenomatous polyposis syndrome (Al-Tassan 2002, Nielsen 2009, Ruggieri 2013), and is enriched in patients with an odds ratio of 6.47 (Theodoratou 2010). Functional characterization of the variant protein indicates a partial reduction in DNA binding and glycosylase activity (Ali 2008, D'Agostino 2010, Goto 2010, Komine 2015, Kundu 2009, Molatore 2010, Ruggieri 2013). Based on available information, this variant is considered to be pathogenic. References: Ali M et al. Characterization of mutant MUTYH proteins associated with familial colorectal cancer. Gastroenterology. 2008 135(2):499-507. Al-Tassan N et al. Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Nat Genet. 2002 30(2):227-32. D'Agostino V et al. Functional analysis of MUTYH mutated proteins associated with familial adenomatous polyposis. DNA Repair (Amst). 2010 9(6):700-7. Goto M et al. Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer. Hum Mutat. 2010 31(11):E1861-74. Komine K et al. Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain. Hum Mutat. 2015 36(7):704-11. Kundu S et al. Adenine removal activity and bacterial complementation with the human MutY homologue (MUTYH) and Y165C, G382D, P391L and Q324R variants associated with colorectal cancer. DNA Repair (Amst). 2009 8(12):1400-10. Molatore S et al. MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay. Hum Mutat. 2010 31(2):159-66. Nielsen M et al. Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis. Gastroenterology. 2009 136(2):471-6. Ruggieri V et al. Loss of MUTYH function in human cells leads to accumulation of oxidative damage and genetic instability. Oncogene. 2013 32(38):4500-8. Theodoratou E et al. A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. Br J Cancer. 2010 Dec 7;103(12):1875-84.
Fulgent Genetics,Fulgent Genetics RCV000515320 SCV000611285 pathogenic MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2017-05-18 criteria provided, single submitter clinical testing
Counsyl RCV000005614 SCV000678192 pathogenic MYH-associated polyposis 2015-07-01 criteria provided, single submitter clinical testing
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
Mayo Clinic Laboratories, Mayo Clinic RCV000079501 SCV000691947 pathogenic not provided 2021-03-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000005614 SCV000697670 pathogenic MYH-associated polyposis 2021-08-13 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1187G>A (p.Gly396Asp) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.003 in 250814 control chromosomes in the gnomAD database, including 3 homozygotes. c.1187G>A has been reported in the literature in multiple individuals affected with MUTYH-Associated Polyposis (example: Castillejo_2014, DeLellis_2013, Ricci_2016). These data indicate that the variant is very likely to be associated with disease. 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 (example: Goto_2010, Komine_2015, Kundu_2009). 32 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000005614 SCV000781800 pathogenic MYH-associated polyposis 2016-11-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000079501 SCV000806339 pathogenic not provided 2016-03-22 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115748 SCV000821744 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This sequence change replaces Glycine with Aspartic acid at codon 396 of the MUTYH protein. The glycine residue is highly conserved in the Nudix Hydrolase domain of the protein and there is a moderate physiochemical difference between glycine and aspartic acid (Grantham Score 94).This variant is present in population databases (rs36053993, 0.4%) and has been reported in the literature. This variant has been reported to co-segregate with disease in patients affected with colorectal cancer, familial adenomatous polyposis (FAP), and attenuated FAP (PMID: 31159747, 19793053, 11818965 ) when found in the homozygous state or in compound heterozygosis with another MUTYH pathogenic variant. This variant is also known as c.1145G>A (p.Gly382Asp) in the literature. Experimental studies have shown that this missense change disrupts MUTYH protein function (PMID: 20848659 ; 15987719). The mutation databaseClinVar contains entries for this variant (Variation ID:5294).
Mendelics RCV000005614 SCV000837751 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000005614 SCV000993433 pathogenic MYH-associated polyposis 2019-12-18 criteria provided, single submitter research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000079501 SCV001248078 pathogenic not provided 2021-04-01 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000005614 SCV001423820 pathogenic MYH-associated polyposis 2019-05-26 criteria provided, single submitter research
Institute of Human Genetics, University of Leipzig Medical Center RCV001262769 SCV001440759 pathogenic Ovarian carcinoma 2019-01-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000079501 SCV001447077 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000079501 SCV001449666 pathogenic not provided 2017-01-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV000005614 SCV001482742 pathogenic MYH-associated polyposis 2020-12-04 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000005614 SCV001499746 pathogenic MYH-associated polyposis 2020-04-02 criteria provided, single submitter clinical testing
Genomics England Pilot Project,Genomics England RCV000005614 SCV001760033 pathogenic MYH-associated polyposis criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000005614 SCV001934278 likely pathogenic MYH-associated polyposis 2020-08-31 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
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.
GeneReviews RCV000005614 SCV000057867 pathogenic MYH-associated polyposis 2019-10-08 no assertion criteria provided literature only
ITMI RCV000121598 SCV000085795 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144637 SCV000189964 pathogenic Carcinoma of colon 2014-07-24 no assertion criteria provided clinical testing
Endocrine oncology group, Uppsala University RCV000493920 SCV000536689 likely pathogenic Small intestine carcinoid 2017-03-09 no assertion criteria provided case-control
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000144637 SCV000592711 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Gly396Asp variant was identified in 102 of 1112 proband chromosomes (frequency: 0.092) from individuals or families with colorectal cancer or MUTYH-associated polyposis, and was not identified in 264 control chromosomes from healthy individuals (Eliason 2006, Nielsen 2009, Sieber 2003). The p.Gly396Asp variant was also identified by our laboratory in 22 individuals with colorectal cancer or polyposis. The p.Gly396Asp variant was identified in dbSNP (ID:rs36053993 ) “With pathogenic allele”, with a minor allele frequency of 0.004 (1000 Genomes Project ), NHLBI Exome Sequencing Project (Exome Variant Server) in 50 of 13006 alleles (frequency: 0.004), HGMD, the “InSiGHT Colon Cancer Database”, and UMD (518X as a causal variant; co-occurring with 14 different pathogenic variants). The p.Gly396Asp variant was classified as a pathogenic variant by multiple submitters to the ClinVar database, including OMIM, GeneReviews, and Emory Genetics. The p.Gly396Asp variant occurs in the first base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing and in-silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a significant difference in splicing. The p.Gly396 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Gly396Asp variant may impact the protein. In vitro assays using synthetic DNA substrates showed that the variant protein reduced adenine removal activity as compared to the wild-type protein and was partially active in DNA binding, base excision repair (BER) and glycosylase activities (Ali 2008, D'Agostino 2010). Two bacterial or mammalian cell-based studies by Kundu (2009) and Molatare (2009) found that the glycosylase activity of the p.Gly396Asp variant did not differ significantly from wild-type; however, Kundu (2009) suggests that the activity of the variant may be more reduced in human cells. Nielsen (2009) identified that although the phenotypic effects of the variant are relatively mild, there is a significantly greater colorectal cancer hazard for patients who were compound heterozygotes for this and a variant with truncating or certain other missense mutations. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic
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.
True Health Diagnostics RCV000115748 SCV000788060 pathogenic Hereditary cancer-predisposing syndrome 2017-12-29 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000005614 SCV000840099 not provided MYH-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.
GenomeConnect - Invitae Patient Insights Network RCV000005614 SCV001716323 not provided MYH-associated polyposis no assertion provided phenotyping only Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 10/09/20 by Invitae and 11/4/14 by Ambry Genetics GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000079501 SCV001744816 pathogenic not provided no assertion criteria provided clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001574076 SCV001797301 pathogenic Breast carcinoma 2021-08-20 no assertion criteria provided clinical testing Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001580144 SCV001805860 pathogenic Malignant tumor of colon 2021-08-23 no assertion criteria provided clinical testing Colon Cancer

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