1-45332167-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001048174.2(MUTYH):c.848G>A(p.Arg283Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,614,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R283S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense, splice_region

Scores

Splicing: ADA: 0.0001072

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:18

Conservation

PhyloP100: 0.267

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:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03441319).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.848G>A	p.Arg283Lys	missense_variant, splice_region_variant	Exon 10 of 16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 link	c.848G>A	p.Arg283Lys	missense_variant, splice_region_variant	Exon 10 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1436G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

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:

0.000111

AC:

AN:

251388

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000643

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000806

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000210

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000700

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:7

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with lysine at codon 311 of the MUTYH protein. This variant is also known as NM_001048171.1:c.890G>A (p.Arg297Lys) in the literature. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with colon, ovarian, breast and lung cancer (PMID: 25186627, 26689913, 27978560, 33471991, 35668106) as well as in an individual potentially biallelic and affected with MUTYH-associated polyposis (PMID: 34704405). This variant has been identified in 36/282768 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 311 of the MUTYH protein (p.Arg311Lys). This variant is present in population databases (rs149342980, gnomAD 0.08%). This missense change has been observed in individual(s) with ovarian, breast, colon cancer and colorectal polyposis (PMID: 25186627, 26689913, 27978560, 35264596, 35668106). This variant is also known as c.890G>A (p.Arg297Lys). ClinVar contains an entry for this variant (Variation ID: 182694). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 30, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:4

Dec 12, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 05, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 c.932G>A, located in exon 10 of the MUTYH gene, is predicted to result in the substitution of arginine by lysine at codon 311, p.(Arg311Lys). This variant is found in 34/268288 alleles at a frequency of 0.012% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.24) suggests that it does not affect the protein function (BP4). To our knowledge, no well-established functional studies have been reported for this variant. This variant has been found in multiple cancer patients (PMID: 35668106, 34704405, 34326862, 33939675, 26689913, 27978560, 33471991, 35264596). This variant has been reported in the ClinVar database (15x uncertain significance) and in LOVD (2x unclassified). Based on currently available information, the variant c.932G>A should be considered an uncertain significance variant, according to ACMG/AMP Guidelines. -

May 21, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R311K variant (also known as c.932G>A), located in coding exon 10 of the MUTYH gene, results from a G to A substitution at nucleotide position 932. The arginine at codon 311 is replaced by lysine, an amino acid with highly similar properties. This alteration was reported in the germline of an individual with ovarian cancer from a cohort of 4034 individuals with cancer undergoing whole exome sequencing (Lu C et al. Nat. Commun. 2015 Dec;6:10086). This variant was observed in an individual diagnosed with breast cancer greater than age 50 and was considered low-risk based on family history (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration has also been identified in a female proband diagnosed at age 37 with colon cancer and in a female proband diagnosed with colorectal cancer in her 60s, but no co-occurring pathogenic variants in MUTYH were reported for either patient (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Georgeson P et al. Nat Commun, 2022 06;13:3254). This amino acid position is not well conserved in available vertebrate species, and lysine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided

Uncertain:3

Oct 25, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a pathogenic MUTYH variant, phase (cis or trans) unknown, in a patient with suspected MUTYH-associated polyposis; however, other variants in MUTYH and other genes were also identified in this patient (PMID: 34704405); Observed in individuals with ovarian, lung, breast, or colorectal cancer (PMID: 26689913, 25186627, 27978560, 33471991, 35264596, 35668106); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as c.890G>A, p.(R297K); This variant is associated with the following publications: (PMID: 26689913, 27978560, 25186627, 33471991, 35264596, 35668106, 34326862, 36672847, 11092888, 11160897, 16879101, 20816984, 34704405, 33939675) -

Feb 20, 2017

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MUTYH c.932G>A (p.Arg311Lys) variant has been reported in the published literature in individuals affected with colorectal cancer (PMIDs: 35668106 (2022), 27978560 (2016)), polyposis (PMID: 34704405 (2021)), breast cancer (PMID: 35264596 (2022), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared), 25186627 (2015)), pancreatic cancer (PMID: 33939675 (2021)), ovarian cancer (PMID: 26689913 (2015)), and lung cancer (PMID: 26689913 (2015)). This variant has also been observed in reportedly healthy individuals (PMIDs: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared), 37306523 (2023)). The frequency of this variant in the general population, 0.0008 (20/24940 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MUTYH c.932G>A (p.Arg311Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251388 control chromosomes, predominantly at a frequency of 0.00074 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00011 vs 0.0046), allowing no conclusion about variant significance. c.932G>A has been reported in the literature in individuals affected with different types of cancers including Colorectal Cancer, Pancreatic Cancer, Breast Cancer and other unspecified cancer (example, Tung_2015, Lu_2015, Pearlman_2016, Zhu_2021, Guindalini_2022, Bhai_2021). It has also been reported in both case and control cohorts of a large case-control study of Breast Cancer (Dorling_2021. 3/60466 cases vs 5/53461 controls). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 35264596, 26689913, 27978560, 25186627, 33939675, 33471991). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Gastric cancer;C3272841:Familial adenomatous polyposis 2

Uncertain:1

Jun 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neoplasm of stomach;C0206711:Pilomatrixoma;C3272841:Familial adenomatous polyposis 2

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.048

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

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.77

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

M_CAP

Benign

0.030

MetaRNN

Benign

0.034

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

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.59

.;.;.;.;.;N;.;.;.;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.44

N;N;N;N;N;N;N;N;N;.;N

REVEL

Benign

0.24

Sift

Benign

0.34

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

Sift4G

Benign

0.59

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

Polyphen

0.0

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

Vest4

0.26

MVP

0.88

MPC

0.11

ClinPred

0.0034

GERP RS

1.7

Varity_R

0.14

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.020

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