NM_001128425.2:c.241G>C

Variant names:

• chr1-45333520-C-G
• rs946755892
• NM_001128425.2:c.241G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_001128425.2(MUTYH):​c.241G>C​(p.Val81Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. V81F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MUTYH NM_001128425.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.307
• Publications: 2 publications found

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

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 62 uncertain in NM_001128425.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10889062).
• BP6: Variant 1-45333520-C-G is Benign according to our data. Variant chr1-45333520-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 648908.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	NM_001128425.2	MANE Plus Clinical	c.241G>C	p.Val81Leu	missense	Exon 3 of 16	NP_001121897.1
	MUTYH	NM_001048174.2	MANE Select	c.157G>C	p.Val53Leu	missense	Exon 3 of 16	NP_001041639.1
	MUTYH	NM_012222.3		c.232G>C	p.Val78Leu	missense	Exon 3 of 16	NP_036354.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.241G>C	p.Val81Leu	missense	Exon 3 of 16	ENSP00000518552.2
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.157G>C	p.Val53Leu	missense	Exon 3 of 16	ENSP00000407590.2
	MUTYH	ENST00000372098.7	TSL:1	c.232G>C	p.Val78Leu	missense	Exon 3 of 16	ENSP00000361170.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:1

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the MUTYH protein (p.Val81Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 648908). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine 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.

Hereditary cancer-predisposing syndrome Benign:1

Sep 09, 2025

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.31
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.0070
Sift	Benign	0.068	T
Sift4G	Benign	0.33	T
Polyphen		0.021	B
Vest4		0.064
MutPred		0.32		Gain of helix (P = 0.132)
MVP		0.50
MPC		0.11
ClinPred		0.35	T
GERP RS		2.7
Varity_R		0.045
gMVP		0.22
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs946755892; hg19: chr1-45799192;