Submissions for variant NM_001048174.2(MUTYH):c.650G>A (p.Arg217His)

gnomAD frequency: 0.00009  dbSNP: rs140342925

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129105	SCV000183816	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-08	criteria provided, single submitter	clinical testing	The p.R245H pathogenic mutation (also known as c.734G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 734. The arginine at codon 245 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in both the homozygous and compound heterozygous state in multiple individuals with colon polyposis and/or colorectal cancer (Aceto G et al. Hum. Mut. 2005 Oct;26:394; Russell AM et al. Int. J. Cancer. 2006 Apr;118:1937-40; Piccioli P et al. Clin. Chem. 2006 Apr;52:739-43; Olschwang S et al. Genet. Test. 2007;11:315-20; Jones N et al. Gastroenterology. 2009 Aug;137:489-94, 494.e1; quiz 725-6; Vogt S et al. Gastroenterology. 2009 Dec;137:1975-85; Morak M et al. Clin Genet, 2010 Oct;78:353-63; Win AK et al. Gastroenterology. 2014 May;146:1208-11.e1-5; Papp J et al. Fam. Cancer. 2016 Jan;15:85-97; Kacerovska D et al. Am. J. Dermatopathol. 2016 Dec;38:915-92; Ricci MT et al. J Hum Genet, 2017 Feb;62:309-315; Viel A et al. EBioMedicine, 2017 Jun;20:39-49; Yanus GA et al. Clin. Genet. 2018 May;93:1015-1021; Sutcliffe EG et al. Fam Cancer, 2019 04;18:203-209; Staninova-Stojovska M et al. Balkan J Med Genet, 2019 Dec;22:5-16). Functional studies have shown that the p.R245H mutation, which exists in the highly conserved and catalytic domain of MUTYH, results in severely defective glycosylase activity, severely defective DNA binding activity, and protein expression levels roughly half of that compared to wild-type (Ali M et al. Gastroenterology. 2008 Aug;135:499–507; Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). Of note, this alteration is also designated as p.R231H (c.692G>A) in published literature. Based on the available evidence to date, this alteration is classified as a pathogenic mutation.
GeneDx	RCV000212706	SCV000211405	pathogenic	not provided	2022-01-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Arg231His; This variant is associated with the following publications: (PMID: 16134147, 16287072, 23108399, 24569162, 19732775, 24444654, 25980754, 26694661, 16557584, 28087410, 18534194, 25820570, 17949294, 16455870, 17081686, 26446593, 28551381, 27783336, 27870730, 27829682, 28152038, 26556299, 31159747, 30604180, 30564557, 29625052, 31263571, 29406563, 34426522, 31589614, 32338768, 30787465, 11801590)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196778	SCV000253868	pathogenic	Familial adenomatous polyposis 2	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 245 of the MUTYH protein (p.Arg245His). This variant is present in population databases (rs140342925, gnomAD 0.03%). This missense change has been observed in individual(s) with familial adenomatous polyposis and colorectal cancer (PMID: 16134147, 16557584, 19732775, 23108399, 24444654, 26446593). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.692G>A (p.Arg231His). ClinVar contains an entry for this variant (Variation ID: 140877). 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: 17081686, 18534194, 23108399, 24569162, 25820570). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000196778	SCV000487344	likely pathogenic	Familial adenomatous polyposis 2	2016-03-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129105	SCV000537663	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 245 of the MUTYH protein. This variant is also known by an alternative transcript, NM_001048171, as c.692G>A (p.Arg231His). A different variant affecting the same codon, c.733C>T (p.Arg245Cys), is considered to be disease-causing (ClinVar variation ID: 41761). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies found this variant to be defective in glycosylase assays (PMID: 18534194, 23108399) and caused abnormal increase in DNA 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and mutation frequency (PMID: 23108399, 24569162). This variant has been reported in multiple individuals who are heterozygous and homozygous carriers and affected with polyposis and colorectal cancer (PMID: 16134147,19394335, 19732775, 23108399, 25590978, 29406563, 29967336, 34704405). This variant has been identified in 24/281670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212706	SCV000601660	pathogenic	not provided	2021-11-19	criteria provided, single submitter	clinical testing	The variant has been reported as homozygous or compound heterozygous in multiple individuals with MAP in the published literature (PMID: 23108399 (2013), 19732775 (2009), 16557584 (2006), 16134147 (2005)). Experimental studies indicate the variant is damaging to MUTYH protein function (PMID: 24569162 (2014), 23108399 (2013), 18534194 (2008)). Based on the available information, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000515198	SCV000611287	pathogenic	Familial adenomatous polyposis 2; Pilomatrixoma; Neoplasm of stomach	2017-05-18	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000129105	SCV000821746	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a missense mutation replacing Arginine with Histidine in the position 245 of the MUTYH protein. This particular Arginine is highly conserved and located in a functional domain of the protein (FeS cluster domain). However there is no significant physicochemical difference between Arginine and Histidine (Grantham Score 29). The aforementioned variant has been described in literature both in homozygosity and heterozygosity in patients with MUTYH-associated polyposis (PMID: 17949294 , PMID: 16287072, PMID: 16134147). Furthermore published functional studies have shown that the variant affects MUTYH protein functionality (PMID: 18534194, PMID: 23108399).This mutation is present at low frequency in population databases (rs140342925, 0.01%). The mutation database ClinVar contains an entry for this variant (Variation ID: 140877).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000196778	SCV000919794	pathogenic	Familial adenomatous polyposis 2	2017-09-07	criteria provided, single submitter	clinical testing	Variant summary: The MUTYH c.734G>A (p.Arg245His) variant causes a missense change involving the alteration of a conserved nucleotide located in the DNA glycosylase domain and the Helix-turn-helix, base-excision DNA repair, C-terminal domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional assays showed the variant to be associated with defective glycosylase and DNA binding activity and concluded that this variant is functionally defective (Ali_2008, Komine_2015).The variant was found in the control population dataset of ExAC in 16/119648 control chromosomes at a frequency of 0.0001337, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). This variant has been reported in numerous MUTYH-associated polyposis patients, in both homozygotes and compound heterozygotes (Aceto_2005, Vogt_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000196778	SCV001368153	pathogenic	Familial adenomatous polyposis 2	2019-05-27	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262379	SCV001440223	likely pathogenic	Breast carcinoma	2019-01-01	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000212706	SCV001449871	pathogenic	not provided	2017-03-09	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000196778	SCV001499744	pathogenic	Familial adenomatous polyposis 2	2020-04-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212706	SCV002011054	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000196778	SCV002017633	pathogenic	Familial adenomatous polyposis 2	2021-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129105	SCV002532325	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-19	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000212706	SCV002544276	pathogenic	not provided	2022-05-01	criteria provided, single submitter	clinical testing	MUTYH: PS3:Very Strong, PS4, PP3
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV003313780	SCV004012921	pathogenic	Diffuse midline glioma, H3 K27-altered	2021-02-26	criteria provided, single submitter	research
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212706	SCV004025001	likely pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000196778	SCV004198928	pathogenic	Familial adenomatous polyposis 2	2024-03-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000196778	SCV004839195	pathogenic	Familial adenomatous polyposis 2	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 245 of the MUTYH protein. This variant is also known by an alternative transcript, NM_001048171, as c.692G>A (p.Arg231His). A different variant affecting the same codon, c.733C>T (p.Arg245Cys), is considered to be disease-causing (ClinVar variation ID: 41761). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies found this variant to be defective in glycosylase assays (PMID: 18534194, 23108399) and caused abnormal increase in DNA 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and mutation frequency (PMID: 23108399, 24569162). This variant has been reported in multiple individuals who are heterozygous and homozygous carriers and affected with polyposis and colorectal cancer (PMID: 16134147,19394335, 19732775, 23108399, 25590978, 29406563, 29967336, 34704405). This variant has been identified in 24/281670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000196778	SCV004848008	pathogenic	Familial adenomatous polyposis 2	2019-12-11	criteria provided, single submitter	clinical testing	The p.Arg245His variant in MUTYH has been reported in 1 homozygous individual, 2 heterozygous individuals, and 10 compound heterozygous individuals with MUTYH-related tumors (Aceto 2005, Olschwang 2007, Russell 2006, Vogt 2009, Win 2014, Yurgelun 2015). It segregated with disease in 3 affected relatives from 2 families (Vogt 2009). It has also been identified in 0.03% (5/19802) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the carrier frequency of MUTYH-related attenuated familial adenomatous polyposis (FAP) in the general population. This variant has been reported in ClinVar (Variation ID: 140877). Functional studies provide some evidence that the p.Arg245His variant has impaired function in vitro (Ali 2008, Ruggieri 2013, Grasso 2014, Komine 2015). In summary, this variant meets criteria to be classified as pathogenic for MUTYH-related attenuated FAP in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Moderate.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129105	SCV005045450	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-12	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000212706	SCV005199297	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353906	SCV000592696	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MUTYH p.Arg245His variant was identified in 15 (2 homozygous, remainder were compound heterozygous) of 3360 proband chromosomes (frequency: 0.004) from individuals or families with MUTYH-associated adenomatous polyposis, familial adenomatous polyposis, or Lynch syndrome and was present in 1 of 2440 control chromosomes (frequency: 0.0004) from healthy individuals (Ruggieri 2013, Vogt 2009, Aceto 2005, Russell 2006, Yanus 2018, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs140342925) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and three other submitters; and classified as likely pathogenic by three submitters), COGR, and UMD-LSDB (23x as causal variant; co-occurring with multiple pathogenic MUTYH mutations). The variant was not identified in Cosmic or MutDB. The variant was identified in control databases in 22 of 276400 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: East Asian in 5 of 18840 chromosomes (freq: 0.0003), Other in 1 of 6454 chromosomes (freq: 0.0002), European in 15 of 126098 chromosomes (freq: 0.0001), and African in 1 of 23930 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish, Finnish, Latino, or South Asian populations. The p.Arg245 residue is conserved across mammals and other organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Multiple studies have demonstrated that the p.Arg245His variant has functionally reduced or abolished DNA binding and glycosylase activity (Ali 2008, Komine 2015, Ruggieri 2013, Grasso 2014). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001262379	SCV001805831	likely pathogenic	Breast carcinoma	2021-08-21	no assertion criteria provided	clinical testing	Invasive Breast Carcinoma EST= + PRO = - HER2 = - KI = 60-70%
PreventionGenetics, part of Exact Sciences	RCV004532545	SCV004116023	pathogenic	MUTYH-related disorder	2023-11-22	no assertion criteria provided	clinical testing	The MUTYH c.734G>A variant is predicted to result in the amino acid substitution p.Arg245His. This variant has been reported in the homozygous and compound heterozygous state in multiple patients to be causative for autosomal recessive adenomatous polyposis coli (sometimes reported as c.692G>A; p.Arg231His in Aceto et al. 2005. PubMed ID: 16134147; Kacerovska et al. 2016. PubMed ID: 27870730; Vogt et al. 2009. PubMed ID: 19732775). Functional studies of the p.Arg245His variant demonstrate that it is deficient in enzymatic and DNA binding activities (Ali et al. 2008. PubMed ID: 18534194), and that it is associated with a statistically significant increase in spontaneous mutation frequency in both homozygous and monoallelic heterozygous lymphoblastoid cell lines derived from MUTYH-associated polyposis patients (Grasso et al. 2014. PubMed ID: 24569162). This variant is reported in 0.025% of alleles in individuals of East Asian descent in gnomAD and has been interpreted as likely pathogenic and pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/140877/). This variant is interpreted as pathogenic.
GenomeConnect - Invitae Patient Insights Network	RCV000196778	SCV004228643	not provided	Familial adenomatous polyposis 2		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 11-25-2019 by Lab Invitae. 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. Phenotypic details are available under supporting information.