Total submissions: 68
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000079501 | SCV000111383 | pathogenic | not provided | 2018-02-27 | criteria provided, single submitter | clinical testing | |
Gene |
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 | 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 | 2022-04-07 | 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, |
RCV000005614 | SCV000245638 | pathogenic | Familial adenomatous polyposis 2 | 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, |
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, |
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, |
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, |
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, |
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, |
RCV000115748 | SCV000679736 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-05-23 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
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, |
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, |
RCV000005614 | SCV000781800 | pathogenic | Familial adenomatous polyposis 2 | 2016-11-01 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV003389664 | SCV000806339 | pathogenic | MUTYH-related condition | 2024-02-21 | criteria provided, single submitter | 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. |
Gene |
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 | |
Hudson |
RCV000005614 | SCV000993433 | pathogenic | Familial adenomatous polyposis 2 | 2019-12-18 | criteria provided, single submitter | research | |
Ce |
RCV000079501 | SCV001248078 | pathogenic | not provided | 2024-02-01 | criteria provided, single submitter | clinical testing | MUTYH: PP1:Strong, PS3, PS4, PM1, PP3 |
Hudson |
RCV000005614 | SCV001423820 | pathogenic | Familial adenomatous polyposis 2 | 2019-05-26 | criteria provided, single submitter | research | |
Institute of Human Genetics, |
RCV001262769 | SCV001440759 | pathogenic | Ovarian carcinoma | 2019-01-01 | criteria provided, single submitter | clinical testing | |
Institute of Medical Genetics and Applied Genomics, |
RCV000079501 | SCV001447077 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Clinical Genetics and Genomics, |
RCV000079501 | SCV001449666 | pathogenic | not provided | 2017-01-04 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000005614 | SCV001482742 | pathogenic | Familial adenomatous polyposis 2 | 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, |
RCV000005614 | SCV001499746 | pathogenic | Familial adenomatous polyposis 2 | 2020-04-02 | criteria provided, single submitter | clinical testing | |
Genomics England Pilot Project, |
RCV000005614 | SCV001760033 | pathogenic | Familial adenomatous polyposis 2 | criteria provided, single submitter | clinical testing | ||
Institute of Human Genetics, |
RCV000005614 | SCV001934278 | likely pathogenic | Familial adenomatous polyposis 2 | 2020-08-31 | criteria provided, single submitter | clinical testing | |
Institute for Clinical Genetics, |
RCV000079501 | SCV002011071 | pathogenic | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000005614 | SCV002017639 | pathogenic | Familial adenomatous polyposis 2 | 2023-07-19 | criteria provided, single submitter | clinical testing | |
Neuberg Supratech Reference Laboratories Pvt Ltd, |
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. |
Ai |
RCV000079501 | SCV002501474 | pathogenic | not provided | 2021-06-04 | criteria provided, single submitter | clinical testing | |
Laboratorio de Genetica e Diagnostico Molecular, |
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 - |
RCV000005614 | SCV002522174 | pathogenic | Familial adenomatous polyposis 2 | 2021-08-06 | criteria provided, single submitter | clinical testing | |
St. |
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, |
RCV000115748 | SCV002532208 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-12-20 | criteria provided, single submitter | curation | |
Laan Lab, |
RCV000005614 | SCV002538610 | pathogenic | Familial adenomatous polyposis 2 | 2021-05-01 | criteria provided, single submitter | research | |
Center for Genomic Medicine, |
RCV000079501 | SCV002547276 | pathogenic | not provided | 2024-02-06 | 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, |
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, |
RCV000005614 | SCV004031104 | pathogenic | Familial adenomatous polyposis 2 | 2023-08-31 | criteria provided, single submitter | clinical testing | |
Genetics and Molecular Pathology, |
RCV000005614 | SCV004175688 | pathogenic | Familial adenomatous polyposis 2 | 2022-04-19 | criteria provided, single submitter | clinical testing | |
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, |
RCV000005614 | SCV000043370 | pathogenic | Familial adenomatous polyposis 2 | 2012-07-13 | no assertion criteria provided | research | Converted during submission to Pathogenic. |
Gene |
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, |
RCV000493920 | SCV000536689 | likely pathogenic | Small intestine carcinoid | 2017-03-09 | no assertion criteria provided | case-control | |
Division of Human Genetics, |
RCV000477907 | SCV000536693 | pathogenic | Familial adenomatous polyposis 2; Neoplasm of stomach | 2015-06-04 | no assertion criteria provided | research | |
Department of Pathology and Laboratory Medicine, |
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, |
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 | |
Genome |
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. | |
Genome |
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, |
RCV000079501 | SCV001744816 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Medical Genetics Laboratory, |
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, |
RCV001580144 | SCV001805860 | pathogenic | Colon cancer | 2021-08-23 | no assertion criteria provided | clinical testing | Colon Cancer |
Clinical Genetics Laboratory, |
RCV000079501 | SCV001977647 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Genome Diagnostics Laboratory, |
RCV000079501 | SCV001977685 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics, |
RCV000079501 | SCV001979292 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Laboratory of Diagnostic Genome Analysis, |
RCV000079501 | SCV001979836 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000079501 | SCV001980277 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000079501 | SCV002037440 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Zotz- |
RCV000005614 | SCV004041729 | pathogenic | Familial adenomatous polyposis 2 | 2023-10-09 | no assertion criteria provided | clinical testing |