chr1-45334422-G-C

Variant names:

• chr1-45334422-G-C
• rs200514222
• NM_001128425.2:c.126C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001128425.2(MUTYH):​c.126C>G​(p.Asn42Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N42S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MUTYH NM_001128425.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0420
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040115476).
• BP6: Variant 1-45334422-G-C is Benign according to our data. Variant chr1-45334422-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533298.

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.126C>G	p.Asn42Lys	missense	Exon 2 of 16	NP_001121897.1
	MUTYH	NM_001048174.2	MANE Select	c.84C>G	p.Asn28Lys	missense	Exon 2 of 16	NP_001041639.1
	MUTYH	NM_012222.3		c.126C>G	p.Asn42Lys	missense	Exon 2 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.126C>G	p.Asn42Lys	missense	Exon 2 of 16	ENSP00000518552.2
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.84C>G	p.Asn28Lys	missense	Exon 2 of 16	ENSP00000407590.2
	MUTYH	ENST00000372098.7	TSL:1	c.126C>G	p.Asn42Lys	missense	Exon 2 of 16	ENSP00000361170.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

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: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

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

Sep 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 42 of the MUTYH protein (p.Asn42Lys). 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: 533298). 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 tolerated. 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	0.092
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.9
DANN	Benign	0.29
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.62	T
PhyloP100		-0.042
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.91	N
REVEL	Benign	0.046
Sift	Benign	1.0	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.18		Loss of ubiquitination at K47 (P = 0.0184)
MVP		0.35
MPC		0.13
ClinPred		0.029	T
GERP RS		-0.89
Varity_R		0.052
gMVP		0.10
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs200514222; hg19: chr1-45800094;