1-45332242-C-T

Position:

chr1-45332242-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001048174.2(MUTYH):c.773G>A(p.Gly258Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,010 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 1 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 7.55

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a helix (size 13) in uniprot entity MUTYH_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001048174.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 1-45332242-C-T is Pathogenic according to our data. Variant chr1-45332242-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45332242-C-T is described in Lovd as [Pathogenic]. Variant chr1-45332242-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2 linkuse as main transcript	c.857G>A	p.Gly286Glu	missense_variant	10/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2 linkuse as main transcript	c.773G>A	p.Gly258Glu	missense_variant	10/16	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.857G>A	p.Gly286Glu	missense_variant	10/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7 linkuse as main transcript	c.773G>A	p.Gly258Glu	missense_variant	10/16	1	NM_001048174.2	ENSP00000407590	A1	Q9UIF7-6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250874

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000478

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:6Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant replaces glycine with glutamic acid at codon 286, in an FeS cluster of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported conflicting results with one complementation of E. coli DNA damage repair (PMID: 25820570) while another study reported impaired DNA repair (PMID: 18422726). This variant has been reported in compound heterozygous individuals affected with MUTYH-associated polyposis (PMID: 17703316, 18422726, 25892863, 28251689, 28533537, 29330641) or pancreatic adenocarcinoma (PMID: 30833417). This variant has also been reported in individuals affected with breast cancer (PMID: 32761968). This variant has been identified in 7/250874 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2017	Variant summary: The MUTYH c.857G>A (p.Gly286Glu) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). A functional study, Yanaru-Fuhisawa_2008, supports these predictions with the observation that the variant impedes DNA glycosylase activity. This variant is absent in 246004 control chromosomes. Multiple publications cite the variant in affected individuals including one pt, who was homozygous for the variant (Yanaru-Fuhisawa_2008) and presented with rectal cancer and colorectal polyposis. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic/pathogenic." Taken together, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 02, 2019	- -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	Found in Japanese & Korean populations -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 286 of the MUTYH protein (p.Gly286Glu). This variant is present in population databases (rs730881833, gnomAD 0.02%). This missense change has been observed in individual(s) with polyposis, colon cancer, and rectal cancer (PMID: 17703316, 18422726, 25892863, 29330641; Invitae). 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.815G>A p.G272E. ClinVar contains an entry for this variant (Variation ID: 182691). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on MUTYH function (PMID: 18422726, 25820570). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MUTYH: PM2, PS3:Moderate, PS4:Moderate, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2022	Published functional studies demonstrate a damaging effect: impaired DNA glycosylase activity (Yanaru-Fujisawa et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28533537, 25931827, 32761968, 25820570, 25892863, 24799981, 23605219, 28251689, 21235684, 28087410, 19953527, 25151137, 17703316, 29330641, 30604180, 30833417, 31360874, 32888815, 32521533, 31742824, 32973888, 30787465, 11092888, 11160897, 18422726) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 25, 2019	This variant has been reported as homozygous and compound heterozygous in multiple individuals with colorectal cancer and/or polyposis in the published literature (PMID: 29330641 (2018), 28533537 (2017), 25892863 (2015), 18422726 (2008)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. Experimental studies have yielded conflicting results regarding the functional impact of this variant (PMID: 25820570 (2015), 18422726 (2008)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 20, 2023	This missense variant replaces glycine with glutamic acid at codon 286, in an FeS cluster of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported conflicting results with one complementation of E. coli DNA damage repair (PMID: 25820570) while another study reported impaired DNA repair (PMID: 18422726). This variant has been reported in compound heterozygous individuals affected with MUTYH-associated polyposis (PMID: 17703316, 18422726, 25892863, 28251689, 28533537, 29330641) or pancreatic adenocarcinoma (PMID: 30833417). This variant has also been reported in individuals affected with breast cancer (PMID: 32761968). This variant has been identified in 7/250874 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 27, 2023	The p.G286E pathogenic mutation (also known as c.857G>A) is located in coding exon 10 of the MUTYH gene. This alteration results from a G to A substitution at nucleotide position 857. The glycine at codon 286 is replaced by glutamic acid, an amino acid with very few similar properties. A Chinese patient with colon cancer diagnosed at age 40 and his sister with colon polyps were found to have this variant in conjunction with another MUTYH alteration, p.Q267* (Zhang JX et al. World J. Gastroenterol. 2015 Apr; 21(14):4136-49). This alteration was reported in a Korean male diagnosed with rectal cancer at age 39 in addition to 36 polyps and it was seen in conjunction with MUTYH p.Q260* in a Japanese patient with 100-200 polyps (Kim DW et al. Int J Colorectal Dis. 2007 Oct;22(10):1173-8; Takao M et al. Int. J. Clin. Oncol. 2018 Jun;23:497-503). This alteration was also reported in conjunction with MUTYH p.S332S in a Chinese patient with pancreatic cancer diagnosed at age 45 and a history of four colorectal adenomatous polyps; her family history was significant for a brother diagnosed with colorectal cancer at age 54 and a total of 30 adenomatous polyps, a sister with multiple colon polyps, and father diagnosed with pancreatic cancer (Thibodeau ML et al. Cold Spring Harb Mol Case Stud. 2019 04;5:). In another study, this alteration was identified in the homozygous state in an individual from Japan diagnosed with adenomatous polyposis as well as five gastric carcinomas and a functional assay demonstrated impaired glycoylase activity (Yanaru-Fujisawa R et al. Clin Genet. 2008 Jun;73(6):545-53). In another functional study, this alteration had mutation suppression levels similar to wild type, but defective glycosylation levels (Komine K et al. Hum. Mutat. 2015 Jul;36(7):704-11). In addition, this variant was detected in the homozygous state in multiple individuals with polyposis by our laboratory (Ambry internal data). Of note, this alteration was previously designated as p.G272E in the literature. 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

0.94

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

.;.;.;.;.;D;.;.;.;T;.;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

5.0

.;.;.;.;.;H;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-7.5

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

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

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

0.97

MutPred

0.94

.;.;.;.;.;.;.;.;Loss of sheet (P = 0.0817);.;.;.;

MVP

0.98

MPC

0.63

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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