rs150792276

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The ENST00000456914.7(MUTYH):c.1192C>T(p.Arg398Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,614,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R398H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00080 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 0 hom. )

Consequence

MUTYH
ENST00000456914.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:9

Conservation

PhyloP100: 0.702

Variant links:

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]

MUTYH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05789399).

BP6

Variant 1-45331467-G-A is Benign according to our data. Variant chr1-45331467-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41753.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=10, Likely_benign=7}. Variant chr1-45331467-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2 linkuse as main transcript	c.1276C>T	p.Arg426Cys	missense_variant	13/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2 linkuse as main transcript	c.1192C>T	p.Arg398Cys	missense_variant	13/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2 linkuse as main transcript	c.1276C>T	p.Arg426Cys	missense_variant	13/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7 linkuse as main transcript	c.1192C>T	p.Arg398Cys	missense_variant	13/16	1	NM_001048174.2	ENSP00000407590	A1	Q9UIF7-6

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000816

AC:

205

AN:

251232

Hom.:

AF XY:

0.000861

AC XY:

117

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000979

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00142

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00136

AC:

1990

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

953

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000937

Gnomad4 NFE exome

AF:

0.00168

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.000802

AC:

122

AN:

152208

Hom.:

Cov.:

AF XY:

0.000713

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00141

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.000861

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000774

AC:

EpiCase

AF:

0.00147

EpiControl

AF:

0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	This variant is associated with the following publications: (PMID: 16134147, 25980754, 30564557, 22703879, 24470512, 16557584, 19531215, 14991577, 22976915, 25820570, 20687945, 21777424, 17524638, 25569433, 27829682, 26976419, 25862857, 27621404, 27498913, 26898890, 16616356, 28944238, 31159747, 33383211, 23108399) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 09, 2022	The frequency of this variant in the general population, 0.0022 (26/11602 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant has been identified in multiple individuals and families affected with various cancers including colorectal cancer (PMID: 28944238 (2017), 30256826 (2018), 30850667 (2019)), colorectal polyposis (PMID: 24470512 (2014), 25980754 (2015), 27829682 (2016)), breast and/or ovarian cancer (PMID: 30564557 (2018), 31159747 (2019), 31921681 (2019)), endometrial cancer (PMID: 27443514 (2016)), pancreatic cancer (PMID: 30151275 (2018)), and lung cancer (PMID: 14991577 (2004)). It has also been found in unaffected individuals (PMID: 16616356 (2006)). An in vitro functional study reports this variant does not have a significant effect MUTYH protein activity, however, this variant’s effect on MUTYH glycosylase activity was not assessed (PMID: 25820570 (2015)). Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 11, 2017	The p.Arg426Cys variant in MUTYH has been reported in at > 8 individuals with co lorectal cancer (Aceto 2005, Aretz 2006, Sulova 2007, Gomez-Fernadez 2009, Lopez -Villar 2010, Guarinos 2014, Yurgelun 2015, Ricci 2017), 2 individuals with brea st cancer (Tung 2016), 1 individual with lung cancer (Al-Tassan 2004) and has a lso been reported by other clinical laboratories in ClinVar (Variation ID 41753) . All individuals reported in the literature were heterozygous and did not carry a second MUTYH variant. This variant has also been identified in 0.1% (184/1266 06) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Althou gh this variant has been seen in the general population, its frequency is not hi gh enough to rule out a pathogenic role. In vitro functional studies provide som e evidence that the p.Arg426Cys variant may not impact protein function (Komine 2015) and computational prediction tools and conservation analysis suggest that the p.Arg426Cys variant may not impact the protein, though this information is n ot predictive enough to rule out pathogenicity. In summary, the clinical signifi cance of the p.Arg426Cys variant is uncertain. ACMG/AMP Criteria applied: BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 29, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 04, 2022	DNA sequence analysis of the MUTYH gene demonstrated a sequence change, c.1276C>T, in exon 13 that results in an amino acid change, p.Arg426Cys. This sequence change has been described in the gnomAD database with a frequency of 0.15% in the non-Finnish European sub-population (dbSNP rs150792276). The p.Arg426Cys change affects a poorly conserved amino acid residue located in a domain of the MUTYH protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg426Cys substitution. The p.Arg426Cys sequence change has been reported in the heterozygous state in multiple individuals with colorectal cancer (PMIDs: 16134147, 16557584, 17524638, 19531215, 20687945, 24470512, 25980754), two individuals with breast cancer (PMID: 26976419), and one individual with lung cancer (PMID: 14579148). Functional studies using a yeast complementation assay demonstrated that MUTYH p.Arg426Cys had base excision repair activity similar to wild-type (PMID: 25820570). Due to these contrasting evidences, the clinical significance of the p.Arg426Cys change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 24, 2024	Variant summary: MUTYH c.1276C>T (p.Arg426Cys) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00081 in 252980 control chromosomes, predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00081 vs 0.0046), allowing no conclusion about variant significance. c.1276C>T has been reported in multiple FAP or attenuated FAP patients in monoallelic state (e.g. Aceto_2005, Aretz_2006, de Lyon_2013, Ricci_2017, Sulova_2009). Furthermore, it has been reported with other pathogenic MUTYH variants in biallelic patients affected with synchronous/metachronous polyps (Lopez-Villar_2010) and colorectal cancer (e.g. De Rycke 2017, Yurgelun 2017). In some of these reports, it was classified as a VUS in settings of multigene cancer panel testing. Additional reports of the variant in individuals with a personal and/or family history of colorectal cancer, HBOC, lung and endometrial cancer have also been published (e.g. Fleischmann_2004, Ricci_2016, Ring_2016, Tung_2016, Martin-Morales_2018, Rizzolo_2018, Oliver_2019, Lin_2019, Tsaousis_2019, Grasel_2020, Pope_2021, Sahin_2022). These data do not allow any conclusion about variant significance. Multiple co-occurrences with other pathogenic variant(s) have been observed at our laboratory (BRCA2 c.4647_4650delAGAG , p.Lys1549fsX18 ; APC c.2161_2170delGGAAGTGCTG, p.Gly721fsX3; MSH6 c.3013C>T, p.Arg1005X; PALB2 c.2386G>T, p.Gly796X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant as evidenced by comparable function to wild-type in terms of suppression of spontaneous mutations (Komine_2015). The following publications have been ascertained in the context of this evaluation (PMID: 22703879, 25820570, 16134147, 16557584, 19531215, 24470512, 20687945, 17524638, 14991577, 26976419, 22976915, 27443514, 28135145, 28944238, 30256826, 30151275, 27829682, 30564557, 30850667, 31159747, 31921681, 31422818, 33383211, 33134171, 35089076, 35430768, 35628513). ClinVar contains an entry for this variant (Variation ID: 41753). Based on the evidence outlined above, the variant was classified as likely benign. -

Familial adenomatous polyposis 2

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 02, 2023	The MUTYH c.1276C>T (p.Arg426Cys) missense change has a maximum subpopulation frequency of 0.15% in gnomAD v2.1.1 and is reported to be homozygous in one individual (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, however a functional assay in E.coli showed that glycosylase repair activity was comparable to the wildtype (PMID: 25820570). This variant has been reported as homozygous in individuals with familial adenomatous polyposis that reportedly did not harbor pathogenic variants in APC (PMID: 16134147, 16557584, 19531215, 20687945). It has also been reported to co-occur with a pathogenic MUYTH pathogenic variant in two individuals with ≥10 adenomas, where one of these individuals also had a personal and family history of colorectal cancer (PMID: 20687945). In addition, this variant has been reported as heterozygous in individuals with familial adenomatous polyposis (PMID: 17524638, 20687945, 22976915, 24470512), colorectal cancer (PMID: 28135145, 28944238, 30256826, 30850667), breast cancer (PMID: 26976419, 30564557), pancreatic cancer (PMID: 30151275), and endometrial cancer (PMID: 27443514). This variant is also known as p.Arg412Cys in the literature. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 25, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 01, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 07, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 27, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Carcinoma of colon

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MUTYH p.Arg426Cys variant was identified in 15 of 6049 proband chromosomes (frequency: 0.003) from individuals or families with FAP, MAP, early onset colorectal cancer or breast cancer and was present in 1 of 1152 control chromosomes (frequency: 0.001) from healthy individuals (Lopez-Villar 2010, Fleischmann 2004, Aceto 2005, Aretz 2006, Kanter-Smoler 2006, Guarinos 2014, DeRycke 2017, Ricci 2017, Tung 2016). In functional complementation tests using E. coli and monitoring spontaneous mutation rates, the variant was found to be functionally retained (Komine 2015). The variant was also identified in dbSNP (ID: rs150792276) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and Ambry Genetics; as uncertain significance by GeneDx and nine other submitters) and in UMD (8x as an unvalidated variant). In UMD the variant was identified with co-occurring pathogenic MUTYH variants c.1145G>A, p.Gly382Asp and c.692G>A, p.Arg231His. The variant was also identified by our laboratory in 5 individuals with colon cancer (no co-occurrence with a pathogenic variant). The variant was identified in control databases in 226 of 277022 chromosomes (1 homozygous) at a frequency of 0.0008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 8 of 24010 chromosomes (freq: 0.0003), Other in 7 of 6454 chromosomes (freq: 0.001), Latino in 8 of 34418 chromosomes (freq: 0.0002), European in 184 of 126606 chromosomes (freq: 0.001), East Asian in 19 of 18866 chromosomes (freq: 0.001); it was not observed in the Ashkenazi Jewish, Finnish, and South Asian populations. The p.Arg426 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

MUTYH-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.54

.;.;.;.;.;.;D;.;.;.;.;D

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.74

.;.;T;.;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.058

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.5

.;.;.;.;.;.;L;.;.;.;.;.

MutationTaster

Benign

0.97

N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-2.3

N;D;D;D;D;D;D;D;D;N;D;.

REVEL

Uncertain

0.61

Sift

Benign

0.036

D;D;D;D;D;D;D;D;D;D;D;.

Sift4G

Uncertain

0.042

D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.0010, 0.012, 0.0

.;.;.;.;.;.;B;B;.;.;B;.

Vest4

0.22

MVP

0.86

MPC

0.15

ClinPred

0.56

GERP RS

1.8

Varity_R

0.18

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over