1-45331556-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong
The NM_001048174.2(MUTYH):c.1103G>A(p.Gly368Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00473 in 1,613,938 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0033 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0049 ( 25 hom. )
Consequence
MUTYH
NM_001048174.2 missense, splice_region
NM_001048174.2 missense, splice_region
Scores
12
5
2
Splicing: ADA: 0.9948
2
Clinical Significance
Conservation
PhyloP100: 4.51
Genes affected
MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
In a strand (size 11) in uniprot entity MUTYH_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_001048174.2
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
Variant 1-45331556-C-T is Pathogenic according to our data. Variant chr1-45331556-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331556-C-T is described in Lovd as [Pathogenic]. Variant chr1-45331556-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-45331556-C-T is described in Lovd as [Pathogenic]. Variant chr1-45331556-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MUTYH | NM_001128425.2 | c.1187G>A | p.Gly396Asp | missense_variant, splice_region_variant | 13/16 | ENST00000710952.2 | NP_001121897.1 | |
| MUTYH | NM_001048174.2 | c.1103G>A | p.Gly368Asp | missense_variant, splice_region_variant | 13/16 | ENST00000456914.7 | NP_001041639.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MUTYH | ENST00000710952.2 | c.1187G>A | p.Gly396Asp | missense_variant, splice_region_variant | 13/16 | NM_001128425.2 | ENSP00000518552 | |||
| MUTYH | ENST00000456914.7 | c.1103G>A | p.Gly368Asp | missense_variant, splice_region_variant | 13/16 | 1 | NM_001048174.2 | ENSP00000407590 | A1 |
Frequencies
GnomAD3 genomes 0.00332 AC: 506AN: 152224Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00303 AC: 756AN: 249742Hom.: 3 AF XY: 0.00300 AC XY: 406AN XY: 135400
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GnomAD4 genome 0.00333 AC: 507AN: 152342Hom.: 1 Cov.: 33 AF XY: 0.00315 AC XY: 235AN XY: 74494
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:68Other:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 2 Pathogenic:29Other:3
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | The c.1187G>A (p.Gly396Asp) variant in the MUTYH gene is located on the exon 13 and is predicted to replace glycine with aspartic acid at codon 396 of the MUTYH protein. This variant has been observed in homozygous or compound heterozygous state in multiple individuals with MUTYH-associated polyposis and colorectal cancer (PMID: 11818965, 12606733, 15635083, 16557584, 19032956, 23108399, 23361220, 25590978, 26202870, 27783336, 28135145, 29147111). This variant has been reported to co-segregate with disease in multiple individuals (PMID: 11818965, 16557584, 17489848, 19793053, 31159747). Experimental studies have shown that this variant affects MUTYH function and leads to a reduction in DNA binding and glycosylase activity (PMID: 11818965, 15036665, 15987719, 18534194, 20418187, 20848659, 22473953, 22926731, 23108399, 25820570). This missense change has been identified in 860/281146 chromosomes in the general population by the Genome Aggregation Database (gnomAD), including three homozygotes. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (REVEL score = 0.954). Based on these evidence, the c.1187G>A (p.Gly396Asp) variant in the MUTYH gene is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 09, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 19, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 01, 2015 | - - |
| Pathogenic, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 13, 2021 | 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. - |
| Pathogenic, no assertion criteria provided | research | Donald Williams Parsons Laboratory, Baylor College of Medicine | Oct 12, 2015 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 20, 2021 | ACMG classification criteria: PS3, PS4, PM3, PP1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jul 05, 2022 | The MUTYH c.1187G>A (p.Gly396Asp) missense change is a well-established pathogenic variant for MUTYH-associated polyposis and is estimated to account for up to 80% of cases in European patients (PMID: 23035301). Although MUTYH-associated polyposis is typically caused by biallelic variants affecting the MUTYH gene, 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). This variant has a maximum subpopulation frequency of 0.49% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies have shown that this missense change disrupts MUTYH protein function (PMID: 15987719, 18534194, 20848659, 23108399). 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). In summary, this variant meets criteria to be classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 19, 2023 | - - |
| Pathogenic, criteria provided, single submitter | research | Laan Lab, Human Genetics Research Group, University of Tartu | May 01, 2021 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | Common pathogenic variants carried by approximately 1%-2% of the general population that account for ≥90% of all MUTYH pathogenic variants in northern European populations; ≤70% of persons with MUTYH-Associated Polyposis (MAP) harbor at least 1 of these variants, 536A>G or 1187G>A - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 22, 2022 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2011 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 31, 2020 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.G396D in MUTYH (NM_001128425.2) has been observed in homozygous or compound heterozygous form with other pathogenic MUTYH variants in patients with adenomatous polyposis syndrome (Al-Tassan 2002, Ruggieri 2013). Functional characterization of the variant protein indicates a partial reduction in DNA binding and glycosylase activity (Ruggieri 2013). The observed variant has been reported in ClinVar as Pathogenic. The p.G396D variant is observed in 555/1,12,884 (0.4917%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and in 9/1,006 (0.8946%) alleles from individuals of European background in 1000 Genomes, which is greater than expected for the disorder. There is a moderate physicochemical difference between glycine and aspartic acid. The p.G396D missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1187 in MUTYH is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | May 26, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health | Aug 06, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 396 of the MUTYH protein (p.Gly396Asp). This variant is present in population databases (rs36053993, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. 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). 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). This variant is also known as c.1145G>A (p.Gly382Asp). ClinVar contains an entry for this variant (Variation ID: 5294). 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 disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 15987719, 18534194, 20848659, 23108399). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 02, 2024 | The p.Gly396Asp variant in MUTYH is a well-established pathogenic variant for MUTYH-related attenuated familial adenomatous polyposis and is estimated to account for 50-82% of MUTYH-associated polyposis in European patients (Al-Tassan 2002 PMID: 11818965, Nielsen 2009 PMID: 17489848, Vogt 2009 PMID: 19732775, Nascimbeni 2010 PMID: 21178863, Aretz 2014 PMID: 23361220, ClinVar: Variation ID 5294). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 5294) and has been identified in 0.5% (367/68040) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2); however, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Gly396Asp variant may impact protein function (Al-Tassan 2002 PMID: 11818965, Ali 2008 PMID: 18534194, Goto 2010 PMID: 20848659). Computational prediction tools and conservation analysis suggest that the p.Gly396Asp variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for MUTYH-associated polyposis in an autosomal recessive manner. The ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PS3_Supporting. - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Dec 18, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | May 31, 2023 | (p.Gly396Asp). This variant is present in population databases (rs36053993, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. 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). MUTYH-related conditions are inherited in an autosomal recessive fashion. However, there is evidence that monoallelic pathogenic MUTYH variants including this particular variant associated with increased risk of colon cancer (PMID: 16492921, 19394335, 21171015, 24444654, 15931596). This variant is also known as c.1145G>A (p.Gly382Asp). ClinVar contains an entry for this variant (Variation ID: 5294). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PoIyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 15987719, 18534194, 20848659, 23108399). For these reasons, this variant has been classified as Pathogenic. Pathogcnic/likely pathogenic mutations in the MUTYH gene are associated with familial polyposis syndrome. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Nov 04, 2022 | ACMG Criteria: PS3, PS4, PM3, PM5, PP3, PP5; Variant was found in heterozygous state. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Intergen, Intergen Genetics and Rare Diseases Diagnosis Center | Aug 31, 2023 | - - |
not provided Pathogenic:19
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 14, 2020 | The MUTYH c.1187G>A (p.Gly396Asp) variant (also known as G396D and G382D) has been reported in the published literature in multiple cases of MUTYH-Associated Polyposis (MAP). This variant is one of two pathogenic variants associated with at least 90% of cases of MAP in patients of European ancestry (PMIDs: 19032956 (2009), 22744763 (2012), 23361220 (2014), 28135145 (2017), 28944238 (2017), 29766397 (2018), 30604180 (2019)). Furthermore, this variant has been described to have a damaging effect on DNA binding and DNA glycosylase activity of the MUTYH protein (PMIDs: 18534194 (2008), 19032956 (2009), 19953527 (2010), 20418187 (2010), 25820570 (2015)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Apr 11, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 27, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 03, 2023 | PP1_strong, PP4, PM3, PS3_supporting, PS4_moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | MUTYH: PS3, PS4, PM1, PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jan 04, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 31, 2022 | 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. PMID: 18534194. 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. PMID: 11818965 D'Agostino V et al. Functional analysis of MUTYH mutated proteins associated with familial adenomatous polyposis. DNA Repair (Amst). 2010 9(6):700-7. PMID: 20418187. 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. PMID: 20848659. 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. PMID: 25820570. 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. PMID: 19836313. 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. PMID: 19953527. Nielsen M et al. Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis. Gastroenterology. 2009 136(2):471-6. PMID: 19032956. 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. PMID: 23108399. 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. PMID: 21063410. - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 04, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2020 | 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) - |
Hereditary cancer-predisposing syndrome Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 06, 2023 | 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 exhibits 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 18, 2023 | The c.1187G>A (p.G396D) alteration is located in coding exon 13 of the MUTYH gene. This alteration results from a G to A substitution at nucleotide position 1187, causing the glycine (G) at amino acid position 396 to be replaced by an aspartic acid (D). Based on data from gnomAD, the A allele has an overall frequency of 0.306% (860/281146) total alleles studied. The highest observed frequency was 0.489% (628/128314) of European (non-Finnish) alleles. This mutation has been identified in a significant percentage of individuals with MUTYH-associated polyposis and represents a founder mutation in multiple populations (Nielsen, 2009). Of the 12 individuals reported as p.G396D homozygotes by these authors, the mean age at clinical presentation was 51 years (range of 36-62). Nine of these 12 individuals had a history of colorectal cancer with a mean age at diagnosis of 58 years (range of 37-70). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.G396D alteration does not affect protein expression or splicing, but results in significantly reduced oxidative DNA mismatch repair efficiency compared to wild type (Plotz, 2012; Raetz, 2012; Ruggieri, 2013). RNA studies have demonstrated this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | True Health Diagnostics | Dec 29, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Vantari Genetics | Dec 21, 2015 | - - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 20, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | May 23, 2018 | - - |
Carcinoma of colon Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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 - |
| Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
Neoplasm of stomach;C3272841:Familial adenomatous polyposis 2 Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Jun 04, 2015 | - - |
Familial colorectal cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 25, 2022 | Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15987719; 18534194; 20848659; 23108399) - PS3_moderate. The c.1187G>A;p.(Gly396Asp)The c.1187G>A;p.(Gly396Asp) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5294; PMID: 23035301; PMID: 19394335; PMID: 21171015; PMID: 24444654; PMID: 15931596) - PS4. The variant co-segregated with disease in multiple affected family members (PMID: 11818965, 16557584, 17489848) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Colorectal adenomatous polyposis, autosomal recessive, with pilomatricomas Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 26, 2016 | - - |
Endometrial cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2011 | - - |
Breast carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 20, 2021 | Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative - |
Small intestine carcinoid Pathogenic:1
| Likely pathogenic, no assertion criteria provided | case-control | Endocrine oncology group, Uppsala University | Mar 09, 2017 | - - |
Ovarian carcinoma Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Neoplasm of stomach;C0206711:Pilomatrixoma;C3272841:Familial adenomatous polyposis 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
MUTYH-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 10, 2024 | The MUTYH c.1187G>A variant is predicted to result in the amino acid substitution p.Gly396Asp. This variant, alternatively described as “G382D or Gly382Asp”, is one of the most common pathogenic variants in MUTYH-associated polyposis (MAP) (Plotz et al. 2012. PubMed ID: 22473953; Olfson et al. 2015. PubMed ID: 26332594; Fabišíková et al. 2020. PubMed ID: 33384714; Daans et al. 2020. PubMed ID: 32088803; Curia et al. 2020. PubMed ID: 32821650). Functional (in vitro) studies of this variant have shown that it negatively affects protein function (Al-Tassan et al. 2002. PubMed ID: 11818965; Goto et al. 2010. PubMed ID: 20848659). However, this variant has been reported with a subpopulation frequency up to ~0.5%, including three homozygotes, in gnomAD. In ClinVar, the vast majority of clinical laboratories have classified this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/5294/). Based on the collective evidence, we interpret this variant as pathogenic. - |
Colon cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 23, 2021 | Colon Cancer - |
not specified Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;.;.;.;D;.;.;.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;.;D;.;D;D;D;D;D;T;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;.;.;.;.;.;H;.;.;.;.;.
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;.
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;.;.;D;D;.;.;D;.
Vest4
MVP
MPC
0.63
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at