Genetic Variant NM_001128425.2:c.821G>C (chr1-45332278-C-G) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_001128425.2(MUTYH):c.821G>C(p.Arg274Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R274Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

MUTYH
NM_001128425.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.88

Publications

33 publications found

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 Gene-Disease associations (from GenCC):

familial adenomatous polyposis 2
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
colorectal cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
familial ovarian cancer
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 38 uncertain in NM_001128425.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-45332278-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41764.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

PP5

Variant 1-45332278-C-G is Pathogenic according to our data. Variant chr1-45332278-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 827517.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128425.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MUTYH	NM_001128425.2	MANE Plus Clinical	c.821G>C	p.Arg274Pro	missense	Exon 10 of 16	NP_001121897.1
MUTYH	NM_001048174.2	MANE Select	c.737G>C	p.Arg246Pro	missense	Exon 10 of 16	NP_001041639.1
MUTYH	NM_012222.3		c.812G>C	p.Arg271Pro	missense	Exon 10 of 16	NP_036354.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MUTYH	ENST00000710952.2	MANE Plus Clinical	c.821G>C	p.Arg274Pro	missense	Exon 10 of 16	ENSP00000518552.2
MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.737G>C	p.Arg246Pro	missense	Exon 10 of 16	ENSP00000407590.2
MUTYH	ENST00000372098.7	TSL:1	c.812G>C	p.Arg271Pro	missense	Exon 10 of 16	ENSP00000361170.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1

Aug 15, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R274P variant (also known as c.821G>C), located in coding exon 10 of the MUTYH gene, results from a G to C substitution at nucleotide position 821. The arginine at codon 274 is replaced by proline, an amino acid with dissimilar properties. In a massively parallel cell-based functional assay testing 7,8-dihydro-8- oxoguanine:adenine (8OG:A) repair activity, a byproduct of oxidative damage, this variant was reported to be non-functional (Hemker SL et al. Am J Hum Genet. Published online July 29, 2025. DOI: 10.1016/j.ajhg.2025.07.005). Another variant at the same codon, p.R274W (c.820C>T), has been reported in the literature in a compound heterozygous state with another MUTYH mutation in multiple individuals with adenomatous polyposis and/or GI cancers (Aceto G et al, Hum. Mutat. 2005 Oct; 26(4):394; Aretz S et al. Int. J. Cancer 2006 Aug;119(4):807-14; Vogt S et al, Gastroenterology 2009 Dec; 137(6):1976-85.e1-10; Aceto GM et al, J. Exp. Clin. Cancer Res. 2015; 34():131). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.85

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.5

PhyloP100

3.9

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.69

MutPred

0.60

Gain of catalytic residue at R274 (P = 0.0191)

MVP

0.99

MPC

0.66

ClinPred

0.99

GERP RS

5.6

PromoterAI

-0.0016

Neutral

(source)

Varity_R

0.96

gMVP

0.88

Mutation Taster

=13/87

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over