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

gnomAD frequency: 0.00341  dbSNP: rs36053993

Total submissions: 73

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000005614	SCV000166443	pathogenic	Familial adenomatous polyposis 2	2024-01-31	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000115748	SCV000184573	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-18	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000005614	SCV000245638	pathogenic	Familial adenomatous polyposis 2	2024-04-02	criteria provided, single submitter	clinical testing	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.
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 Diagnostics, LLC DBA Color Health	RCV000115748	SCV000537630	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-06	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 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.
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	2020-09-14	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000079501	SCV000604306	pathogenic	not provided	2022-10-31	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. 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.
Fulgent Genetics, Fulgent Genetics	RCV000515320	SCV000611285	pathogenic	Familial adenomatous polyposis 2; Pilomatrixoma; Neoplasm of stomach	2017-05-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000005614	SCV000678192	pathogenic	Familial adenomatous polyposis 2	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	2023-05-03	criteria provided, single submitter	clinical testing	PP1_strong, PP4, PM3, PS3_supporting, PS4_moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000005614	SCV000697670	pathogenic	Familial adenomatous polyposis 2	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	Familial adenomatous polyposis 2	2016-11-01	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	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000005614	SCV000993433	pathogenic	Familial adenomatous polyposis 2	2019-12-18	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000079501	SCV001248078	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	MUTYH: PS3, PS4, PM1, PP3
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000005614	SCV001423820	pathogenic	Familial adenomatous polyposis 2	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 and Genomics, Karolinska University Hospital	RCV000079501	SCV001449666	pathogenic	not provided	2017-01-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000005614	SCV001482742	pathogenic	Familial adenomatous polyposis 2	2024-03-29	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000005614	SCV001499746	pathogenic	Familial adenomatous polyposis 2	2020-04-02	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV000005614	SCV001760033	pathogenic	Familial adenomatous polyposis 2		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000005614	SCV001934278	likely pathogenic	Familial adenomatous polyposis 2	2020-08-31	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000079501	SCV002011071	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000005614	SCV002017639	pathogenic	Familial adenomatous polyposis 2	2023-07-19	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000005614	SCV002073195	pathogenic	Familial adenomatous polyposis 2		criteria provided, single submitter	clinical testing	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.
DASA	RCV002051775	SCV002318970	pathogenic	Familial colorectal cancer	2022-03-25	criteria provided, single submitter	clinical testing	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.
AiLife Diagnostics, AiLife Diagnostics	RCV000079501	SCV002501474	pathogenic	not provided	2021-06-04	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000005614	SCV002512303	pathogenic	Familial adenomatous polyposis 2	2021-12-20	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM3, PP1
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000005614	SCV002522174	pathogenic	Familial adenomatous polyposis 2	2021-08-06	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000005614	SCV002525942	pathogenic	Familial adenomatous polyposis 2	2022-07-05	criteria provided, single submitter	clinical testing	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.
Sema4, Sema4	RCV000115748	SCV002532208	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	curation
Laan Lab, Human Genetics Research Group, University of Tartu	RCV000005614	SCV002538610	pathogenic	Familial adenomatous polyposis 2	2021-05-01	criteria provided, single submitter	research
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000079501	SCV002547276	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000005614	SCV002580176	pathogenic	Familial adenomatous polyposis 2	2022-08-22	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000005614	SCV003927260	pathogenic	Familial adenomatous polyposis 2	2023-05-31	criteria provided, single submitter	clinical testing	(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.
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000005614	SCV004031104	pathogenic	Familial adenomatous polyposis 2	2023-08-31	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000005614	SCV004175688	pathogenic	Familial adenomatous polyposis 2	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000005614	SCV004806971	pathogenic	Familial adenomatous polyposis 2	2024-03-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000005614	SCV004836151	pathogenic	Familial adenomatous polyposis 2	2024-02-05	criteria provided, single submitter	clinical testing	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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000079501	SCV005199293	pathogenic	not provided	2023-04-11	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV004785246	SCV005381829	pathogenic	Diffuse midline glioma, H3 K27-altered	2023-07-26	criteria provided, single submitter	research
Institute of Immunology and Genetics Kaiserslautern	RCV000005614	SCV005382145	pathogenic	Familial adenomatous polyposis 2	2022-11-04	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PS4, PM3, PM5, PP3, PP5; Variant was found in heterozygous state.
OMIM	RCV000005614	SCV000025796	pathogenic	Familial adenomatous polyposis 2	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	Familial adenomatous polyposis 2	2012-07-13	no assertion criteria provided	research	Converted during submission to Pathogenic.
GeneReviews	RCV000005614	SCV000057867	not provided	Familial adenomatous polyposis 2		no assertion provided	literature only	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
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	Familial adenomatous polyposis 2; 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	Familial adenomatous polyposis 2	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
PreventionGenetics, part of Exact Sciences	RCV004528084	SCV000806339	pathogenic	MUTYH-related disorder	2024-09-10	no assertion criteria provided	clinical testing	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.
GenomeConnect, ClinGen	RCV000005614	SCV000840099	not provided	Familial adenomatous polyposis 2		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	Familial adenomatous polyposis 2		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	Colon cancer	2021-08-23	no assertion criteria provided	clinical testing	Colon Cancer
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000079501	SCV001977647	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000079501	SCV001977685	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000079501	SCV001979292	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000079501	SCV001979836	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000079501	SCV001980277	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000079501	SCV002037440	pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000005614	SCV004041729	pathogenic	Familial adenomatous polyposis 2	2023-10-09	no assertion criteria provided	clinical testing