rs587780078

Positions:

• chr1-45331514-T-TCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001048174.2(MUTYH):​c.1143_1144dupGG​(p.Glu382fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E382E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: MUTYH NM_001048174.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22 O:1
• Conservation: PhyloP100: 2.10

Genes affected

MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]

ENSG00000288208 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45331514-T-TCC is Pathogenic according to our data. Variant chr1-45331514-T-TCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 127831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.1143_1144dupGG	p.Glu382fs	frameshift_variant	13/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.1143_1144dupGG	p.Glu382fs	frameshift_variant	13/16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1731_1732dupGG		non_coding_transcript_exon_variant	17/21			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 250940 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1461784 Hom.: 0 Cov.: 33 AF XY: 0.0000523 AC XY: 38 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74348

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000234

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:11 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetics Department, Catlab	Sep 10, 2024	The c.1143_1144dup frameshift variant in the MUTYH gene gene is a loss of function variant predicted to undergo nonsense mediated decay and loss of function variants have been described as a causing mechanism for the gene (PVS1). This change has been previously found in several patients in homozygous and compound heterozygous patients in the literature (PMID: 31739127, 19531215, 22744763) (PM3_Very_strong). Moreover, the variant has a very low frequency in gnomAD 4.1 (AF = 6.9394e-05) (PM2). With all the available evidence, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	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 PMID: 15188161, Vogt 2009 PMID: 19732775, Abdelmaksoud-Dammak 2012 PMID: 22744763, Ruggieri 2013 PMID: 23108399, Yurgelun 2015 PMID: 25980754). It segregated with disease in 2 affected individuals from 2 families (Abdelmaksoud-Dammak 2012 PMID: 2274476). In vitro functional studies provide some evidence that the p.Glu410fs variant may impact protein function (Ruggieri 2013 PMID: 23108399). It has been identified in 30/34416 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs587780078). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence 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 absent protein. Homozygous loss of function of the MUTYH gene is an established disease mechanism in individuals with MAP. In summary, this variant meets criteria 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 23, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	Common in the Spanish, Portuguese, & Tunisian populations -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 15, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 08, 2019	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 30, 2022	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. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 08, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 04, 2024	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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	May 06, 2021	- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

MUTYH-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587780078; hg19: chr1-45797186;