Submissions for variant NM_001048174.2(MUTYH):c.1143_1144dup (p.Glu382fs)

dbSNP: rs587780078

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235187	SCV000149658	pathogenic	not provided	2020-09-21	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21777424, 26681312, 29753700, 26556299, 30256826, 31921681, 23108399, 15366000, 25980754, 25822476, 20687945, 24470512, 28644590, 15188161, 28195393, 28152038, 28577310, 22744763, 19732775, 27829682, 30604180, 31739127, 30291343, 29625052, 31447099, 31589614, 30787465)
Invitae	RCV000191935	SCV000166444	pathogenic	Familial adenomatous polyposis 2	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu410Glyfs*43) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant is present in population databases (rs587780078, gnomAD 0.09%). This premature translational stop signal has been observed in individual(s) with polyposis, colorectal cancer, breast cancer, and cervical cancer (PMID: 15188161, 15366000, 19531215, 19732775). This variant is also known as c.1186_1187insGG (p.Glu396GlyfsX43). ClinVar contains an entry for this variant (Variation ID: 127831). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000115749	SCV000184139	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-25	criteria provided, single submitter	clinical testing	The c.1227_1228dupGG pathogenic mutation, located in coding exon 13 of the MUTYH gene, results from a duplication of GG at nucleotide position 1227, causing a translational frameshift with a predicted alternate stop codon (p.E410Gfs*43). This mutation has been reported in multiple individuals with MUTYH-associated polyposis in both the homozygous and compound heterozygous state (Venesio T et al. Gastroenterology, 2004 Jun;126:1681-5; Isidro G et al. Hum. Mutat., 2004 Oct;24:353-4; Nielsen M et al. J. Med. Genet., 2005 Sep;42:e54; Gómez-Fernández N et al. BMC Med Genet, 2009 Jun;10:57; Vogt S et al. Gastroenterology, 2009 Dec;137:1976-85.e1-10; Lefevre JH et al. Clin Genet, 2011 Oct;80:389-93; Abdelmaksoud-Dammak R et al. Fam. Cancer, 2012 Sep;11:503-8; Venesio T et al. Mod Pathol, 2013 Oct;26:1371-81; Guarinos C et al. Clin Cancer Res, 2014 Mar;20:1158-68; Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20; Ricci MT et al. J Hum Genet, 2017 Feb;62:309-315; Martin-Morales L et al. PLoS One, 2018 Sep;13:e0203885; Sutcliffe EG et al. Fam Cancer, 2019 04;18:203-209; Kdissa A et al. Cancer Genet, 2020 01;240:45-53). Of note, this alteration is also designated as c.1229insGG, c.1186_1187insGG, 1185_1186dupGG, and 1187insGG in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000191935	SCV000678199	pathogenic	Familial adenomatous polyposis 2	2015-10-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115749	SCV000685556	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This variant inserts 2 nucleotides in exon 13 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as c.1185_1186dupGG, c.1186_1187insGG and 1187insGG based on a different transcript (NM_001048171.1). This variant has been reported in multiple individuals affected with polyposis and colorectal cancer in homozygous state (PMID: 15366000, 17122612, 19531215, 19732775) and in compound heterozygous state with a known pathogenic variant in the same gene (PMID: 15188161, 22744763). It has also been reported in multiple individuals affected with polyposis with unspecified genotype (PMID: 27829682). A study of 36 families affected with polyposis has determined this variant to be a founder mutation in the North African population (PMID: 21443744). This variant has also been reported in a heterozygous individual suspected of having Lynch syndrome (PMID: 25980754). This variant has been identified in 40/282334 chromosomes (31/35430 Latino chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000191935	SCV000697671	pathogenic	Familial adenomatous polyposis 2	2016-10-28	criteria provided, single submitter	clinical testing	Variant summary: The MUTYH c.1227_1228dupGG (p.Glu410Glyfs) variant results in a premature termination codon, predicted to cause a truncated or absent MUTYH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic by our laboratory (e.g.c.1435G>T/p.Glu479X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 7/120274 control chromosomes at a frequency of 0.0000582, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). This variant has been reported in numerous MAP patients and colorectal cancer patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000191935	SCV000712103	pathogenic	Familial adenomatous polyposis 2	2016-08-15	criteria provided, single submitter	clinical testing	The p.Glu410fs variant in MUTYH has been previously reported as heterozygous in 2 individuals with Lynch syndrome and as homozygous or compound heterozygous in 11 individuals with MUTYH-associated polyposis (MAP; Venesio 2004, Vogt 2009, Da mmak 2012, Ruggieri 2013, Yurgelun 2015). It segregated with disease in 2 affect ed individuals from 2 families (Dammak 2012). In vitro functional studies provid e some evidence that the p.Glu410fs variant may impact protein function (Ruggier i 2013). It has been identified in 30/34416 Latino chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs587780078) . Although this variant has been seen in the general population, its frequency i s low enough to be consistent with a recessive carrier frequency. This variant i s predicted to cause a frameshift, which alters the protein?s amino acid sequenc e beginning at position 410 and leads to a premature termination codon 43 amino acids downstream. This alteration is then predicted to lead to a truncated or ab sent protein. Homozygous loss of function of the MUTYH gene is an established di sease mechanism in individuals with MAP. In summary, this variant meets criteri a to be classified as pathogenic for FAP in an autosomal recessive manner based upon predicted impact to the protein, presence in multiple affected individuals, and functional studies. ACMG/AMP Criteria applied: PVS1, PS4, PP3_supporting (R ichards 2015).
Eurofins Ntd Llc (ga)	RCV000235187	SCV000859446	pathogenic	not provided	2018-01-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235187	SCV000888298	pathogenic	not provided	2022-08-30	criteria provided, single submitter	clinical testing	The MUTYH c.1227_1228dup (p.Glu410Glyfs*43) variant alters the translational reading frame of the MUTYH mRNA and causes the premature termination of MUTYH protein synthesis. This variant has been reported in the published literature in both homozygous and compound heterozygous state in patients affected with polyposis or colorectal cancer (PMID: 15188161 (2004), 19531215 (2009), 19732775 (2009), 22744763 (2012), 27829682 (2017), 28195393 (2017), and 31739127 (2020)), and breast and/or cervical cancer (PMID: 19732775 (2009)). The frequency of this variant in the general population, 0.00087 (31/35430 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV000191935	SCV000915414	likely pathogenic	Familial adenomatous polyposis 2	2017-04-28	criteria provided, single submitter	clinical testing	The MUTYH c.1185_1186dupGG (p.Glu396GlyfsTer43) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Glu396GlyfsTer43 variant has been reported in two studies in which it is found in a total of three individuals with MYH-associated polyposis, including in two in a compound heterozygous state and in one in a heterozygous state (Nielson et al. 2005; LeJeune et al. 2006). The p.Glu396GlyfsTer43 variant was absent from 50 controls and is reported at a frequency of 0.00043 in the Latino population of the Exome Aggregation Consortium. Based on the evidence and potential impact of frameshift variants, the p.Glu396GlyfsTer43 variant is classified as likely pathogenic for MYH-associated polyposis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Revvity Omics, Revvity	RCV000191935	SCV002017627	pathogenic	Familial adenomatous polyposis 2	2019-09-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115749	SCV002532212	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000191935	SCV004015245	pathogenic	Familial adenomatous polyposis 2	2023-07-07	criteria provided, single submitter	clinical testing	This variant is also known as c.1185_1186dupGG, c.1186_1187insGG and 1187insGG based on a different transcript (NM_001048171.1). In-silico predictions show this variant to be deleterious. This variant has been reported in multiple individuals affected with polyposis and colorectal cancer in homozygous state (PMID: 15366000, 17122612, 19531215, 19732775) or in compound heterozygous state with a known pathogenic variant in the same gene (PMID: 15188161, 22744763). A study of 36 families affected with polyposis has determined this variant to be a founder mutation in the North African population (PMID: 21443744). This variant has been identified in 40/282334 chromosomes (31/35430 Latino chromosomes) in the general population by the Genome Aggregation Database (gnomAD). ClinVar classifies this variant as Pathogenic, rated 2 stars, with 13 submissions, 17 publications (15188161, 15366000, 15690400, 16140997, 16941501 and 12 more) and no conflicts. Null variant (frame-shift), in gene MUTYH for which lossof- function is a known mechanism of disease. Therefore, this variant is classified as Pathogenic.
Baylor Genetics	RCV000191935	SCV004198821	pathogenic	Familial adenomatous polyposis 2	2023-10-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952553	SCV004779967	pathogenic	MUTYH-related condition	2024-02-28	criteria provided, single submitter	clinical testing	The MUTYH c.1227_1228dupGG variant is predicted to result in a frameshift and premature protein termination (p.Glu410Glyfs*43). This variant has been reported in the homozygous and compound heterozygous states in individuals with polyposis (Venesio et al. 2004. PubMed ID: 15188161, reported as 1187insGG; Abdelmaksoud-Dammak et al. 2012. PubMed ID: 22744763). In addition, this variant has been reported in an individual with cervical carcinoma and breast cancer (Vogt et al. 2009. PubMed ID: 19732775). This variant is reported in 0.087% of alleles in individuals of Latino descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127831/). Frameshift variants in MUTYH are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000191935	SCV000025803	pathogenic	Familial adenomatous polyposis 2	2005-04-15	no assertion criteria provided	literature only
Pathway Genomics	RCV000144636	SCV000189963	pathogenic	Carcinoma of colon	2014-07-24	no assertion criteria provided	clinical testing
GeneReviews	RCV000191935	SCV000246167	not provided	Familial adenomatous polyposis 2		no assertion provided	literature only	Common in the Spanish, Portuguese, & Tunisian populations
Clinical Genetics, Academic Medical Center	RCV000235187	SCV001925609	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000235187	SCV001971571	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000235187	SCV002036968	pathogenic	not provided		no assertion criteria provided	clinical testing