1-45331744-C-T

Variant names:

• chr1-45331744-C-T
• rs1060501340
• NM_001128425.2:c.1103G>A

Variant summary

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

The NM_001128425.2(MUTYH):​c.1103G>A​(p.Arg368Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R368G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001128425.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.48
• Publications: 4 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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 23 benign, 57 uncertain in NM_001128425.2
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-45331744-C-T is Benign according to our data. Variant chr1-45331744-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 406855.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1103G>A	p.Arg368Lys	missense_variant	Exon 12 of 16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.1019G>A	p.Arg340Lys	missense_variant	Exon 12 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.1103G>A	p.Arg368Lys	missense_variant	Exon 12 of 16		NM_001128425.2	ENSP00000518552.2
MUTYH	ENST00000456914.7	c.1019G>A	p.Arg340Lys	missense_variant	Exon 12 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1607G>A		non_coding_transcript_exon_variant	Exon 16 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:1

Apr 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 368 of the MUTYH protein (p.Arg368Lys). 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: 406855). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R368K variant (also known as c.1103G>A), located in coding exon 12 of the MUTYH gene, results from a G to A substitution at nucleotide position 1103. The arginine at codon 368 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	.;D;.;D;D;D;D;D;D;D;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.2	.;.;.;.;.;M;.;.;.;.;.
PhyloP100		7.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N;N;N;N;.;N
REVEL	Uncertain	0.51
Sift	Benign	0.097	T;T;T;T;T;T;T;T;T;.;D
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.014, 0.56, 0.42	.;.;.;.;.;B;P;.;B;.;.
Vest4		0.56
MutPred		0.34		.;.;.;.;.;.;.;.;Gain of ubiquitination at R368 (P = 0.0203);.;.;
MVP		0.93
MPC		0.25
ClinPred		0.78	D
GERP RS		5.7
Varity_R		0.39
gMVP		0.72
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060501340; hg19: chr1-45797416;