rs200495564

chr1-45332446-G-Achr1-45332446-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001048174.2(MUTYH):c.649C>T(p.Arg217Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R217H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 U:1
• Conservation: PhyloP100: 7.25

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45332445-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 1-45332446-G-A is Pathogenic according to our data. Variant chr1-45332446-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 41761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45332446-G-A is described in Lovd as [Pathogenic]. Variant chr1-45332446-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.733C>T	p.Arg245Cys	missense_variant	9/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.649C>T	p.Arg217Cys	missense_variant	9/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.733C>T	p.Arg245Cys	missense_variant	9/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.649C>T	p.Arg217Cys	missense_variant	9/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000559 AC: 14 AN: 250276 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135536

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461766 Hom.: 0 Cov.: 36 AF XY: 0.0000220 AC XY: 16 AN XY: 727182

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74478

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000682 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:6

Likely pathogenic, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2021	Variant summary: MUTYH c.733C>T (p.Arg245Cys) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250436 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (5.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.733C>T has been reported in the literature in multiple individuals affected with adenomatous polyposis, either in homozygosity (Miyaki_2005, Olschwang_2007), or in compound heterozygosity with known- or likely pathogenic variants (Ruggieri_2013, Takao_2017, Furlan_2017). Functional studies indicated that the variant mildly diminishes RNA and protein expression, but completely abolishes DNA glycosylase activity (Ruggieri_2013), and partially impairs base excision repair (Komine_2015). Additionally, other variants at this amino acid position are reported in patients (p.Arg245His, p.Arg245Ser and p.Arg245Leu), suggesting this residue is critical for function. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=6) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces arginine with cysteine at codon 245 of the MUTYH protein. This variant is also known as c.691C>T (p.Arg231Cys) based on an alternative transcript (NM_001048171). 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 have reported this variant to be non-functional in MUTYH glycosylase assay (PMID: 23108399) and complementation of MUTYH-deficient bacteria (PMID: 25820570). This variant has been observed as a homozygous variant and compound heterozygous variant with a pathogenic co-variant in individuals affected with colorectal cancer and/or multiple colorectal adenomas and polyps (PMID: 15890374, 17949294, 23108399, 34775073). This variant has also been identified in an individual affected with breast cancer (PMID: 34026625). This variant has been identified in 14/250276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 21, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 245 of the MUTYH protein (p.Arg245Cys). This variant is present in population databases (rs200495564, gnomAD 0.02%). This missense change has been observed in individuals with familial adenomatous polyposis and/or MUTYH-associated polyposis (PMID: 15890374, 17949294, 23108399). This variant is also known as c.691C>T (p.Arg231Cys). ClinVar contains an entry for this variant (Variation ID: 41761). 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: 23108399, 25820570). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 08, 2019	- -

not provided Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2023	Observed in the homozygous or compound heterozygous state in individuals with multiple polyps and colorectal cancer (Miyaki et al., 2005; Olschwang et al., 2007; Ruggieri et al., 2013; Gunaratnam et al., 2016; Furlan et al., 2017; Takao et al., 2018; Villy et al., 2021); Published functional studies demonstrate a damaging effect: absent DNA glycosylase activity, decreased MUTYH transcript and protein expression levels, and partially defective base excision repair (Ruggieri et al., 2013; Komine et al., 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: 23605219, 22744763, 24620956, 19725997, 17949294, 15890374, 22703879, 21443744, 22865608, 25655665, 23108399, 25820570, 26684191, 28087410, 28152038, 30564557, 30787465, 34775073, 32980694, 31739127, 19506731, 17703316, 23507534, 29915346, 11801590, 31203172, 24569162, 31104418, 32821650, 32665031, 27021195, 29330641, 34026625, 34308104, 30487145, 28141798) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 29, 2021	This variant has been reported in multiple unrelated individuals with MUTYH-Associated Polyposis (MAP) and colorectal cancer in the published literature (PMIDs: 28141798 (2017), 23108399 (2013)),17949294 (2007), and 15890374 (2005)). Additionally, functional studies demonstrate a damaging effect of this variant on MUTYH protein function (PMIDs: 23108399 (2013) and 25820570 (2015)). Based on the available information, this variant is classified as pathogenic. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 03, 2022	The p.R245C pathogenic mutation (also known as c.733C>T), located in coding exon 9 of the MUTYH gene, results from a C to T substitution at nucleotide position 733. The arginine at codon 245 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been detected in the homozygous state in both Japanese and Portuguese APC mutation-negative adenomatous polyposis patients (Miyaki M et al. Mutat. Res. 2005 Oct 15;578(1-2):430-3; Olschwang S et al. Genet Test. 2007 Fall;11(3):315-20). This alteration was also seen in conjunction with a second MUTYH mutation in a 37 yo female with a history of colon cancer and approximately 50 colon polyps (Ruggieri V et al. Oncogene, 2013 Sep;32:4500-8). Current evidence supports codon 245 as a functionally important mutation hotspot, with multiple other missense alterations having been described as pathogenic or deficient in critical protein function in the literature (Aceto G et al. Hum Mutat. 2005 Oct;26(4):394; Vogt S et al. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10; Bai H et al. Cancer Lett. 2007 May 18;250(1):74-81). In addition, a functional assay showed that p.R245C, which exists in a highly conserved and catalytic domain, results in partially defective protein expression levels compared to wild-type (Komine K et al. Hum. Mutat., 2015 Jul;36:704-11). Of note, this mutation is also described as p.R231C in published literature. This alteration has been detected in conjunction with a second pathogenic MUTYH mutation in an adenomatous polyposis patient without any detectable APC mutation (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 05, 2023	This missense variant replaces arginine with cysteine at codon 245 of the MUTYH protein. This variant is also known as c.691C>T (p.Arg231Cys) based on an alternative transcript (NM_001048171). 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 have reported this variant to be non-functional in MUTYH glycosylase assay (PMID: 23108399) and complementation of MUTYH-deficient bacteria (PMID: 25820570). This variant has been observed as a homozygous variant and compound heterozygous variant with a pathogenic co-variant in individuals affected with colorectal cancer and/or multiple colorectal adenomas and polyps (PMID: 15890374, 17949294, 23108399, 34775073). This variant has also been identified in an individual affected with breast cancer (PMID: 34026625). This variant has been identified in 14/250276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Familial colorectal cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Snyder Lab, Genetics Department, Stanford University

Jan 01, 2017

- -

Gastric cancer;C3272841:Familial adenomatous polyposis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 19, 2022

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.5	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;D;.;D;.;.;.
Vest4		0.99
MVP		0.98
MPC		0.64
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs200495564; hg19: chr1-45798118; COSMIC: COSV58344430; COSMIC: COSV58344430;