chr1-45331745-T-TG

Variant names:

• chr1-45331745-T-TG
• rs768130289
• NM_001128425.2:c.1101dupC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001128425.2(MUTYH):​c.1101dupC​(p.Arg368GlnfsTer164) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P367P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MUTYH NM_001128425.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.280
• Publications: 6 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45331745-T-TG is Pathogenic according to our data. Variant chr1-45331745-T-TG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 185770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1101dupC	p.Arg368GlnfsTer164	frameshift_variant	Exon 12 of 16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.1017dupC	p.Arg340GlnfsTer164	frameshift_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.1101dupC	p.Arg368GlnfsTer164	frameshift_variant	Exon 12 of 16		NM_001128425.2	ENSP00000518552.2
MUTYH	ENST00000456914.7	c.1017dupC	p.Arg340GlnfsTer164	frameshift_variant	Exon 12 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1605dupC		non_coding_transcript_exon_variant	Exon 16 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250124 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461794 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727200

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:3

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg368Glnfs*164) in the MUTYH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 182 amino acid(s) of the MUTYH protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with attenuated familial adenomatous polyposis and colon and breast cancer (PMID: 16941501, 24953332). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1059dupC (Arg354Glnfs*164). ClinVar contains an entry for this variant (Variation ID: 185770). This variant disrupts the conserved PCNA binding motif of the MUTYH protein, which has been shown to be critical for MUTYH-PCNA binding and repair efficiency (PMID: 11092888, 26377631, 11433026, 11864576). While functional studies have not been performed to directly test the effect of this variant on MUTYH protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 12 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as c.1059dupC (Arg354Glnfs*164). This variant has been observed in biallelic individuals affected with colorectal cancer and/or polyposis (PMID: 16941501, 24953332, 33130102). This variant has been identified in 1/250124 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Oct 15, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MUTYH c.1101dupC (p.Arg368GlnfsX164) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250124 control chromosomes (gnomAD). c.1101dupC has been reported in the literature in compound heterozygous individuals affected with MUTYH-Associated Polyposis or colorectal cancer (e.g. Lejeune_2006, Castillejo_2014, Thomas_2021). In addition, the variant has been reported in heterozygous individuals affected with breast and ovarian cancer (e.g. Bonache_2018, Feliubadalo_2019, Ramirez-Calvo_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:3

Aug 04, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1101dupC pathogenic mutation, located in coding exon 12 of the MUTYH gene, results from a duplication of C at nucleotide position 1101, causing a translational frameshift with a predicted alternate stop codon (p.R368Qfs*164). This alteration occurs at the 3' terminus of theMUTYH gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 3% of the protein. However, premature stop codons are typically deleterious in nature. This alteration has been detected in conjunction with another MUTYH mutation in patients diagnosed with colorectal cancer and/or polyps (Lejeune S. et al. Hum Mutat. 2006 Oct;27(10):1064; Castillejo A et al. Eur J Cancer. 2014 Sep;50(13):2241-50). This alteration as also been detected as monoallelic in patients diagnosed with breast or ovarian cancer (Bonache S et al. J Cancer Res Clin Oncol. 2018 Oct 10). This variant is designated as 1059dupC in published literature. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Oct 23, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM3, PM2_supporting c.1101dup, located in exon 12 of the MUTYH gene, consists in the duplication of 1 nucleotide, causing a translational frameshift with a predicted alternate stop codon, p.(Arg368Glnfs*164). This alteration affects a critical region to protein function and the PTC is created after 532 codon (PVS1). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). In addition, it has been reported in ClinVar (5x as pathogenic, 1x as likely pathogenic) and in LOVD (2x likely pathogenic) databases. This variation has been observed in compound heterozygous state in multiple individuals with MUTYH-Associated Polyposis (PMID: PMID: 24953332, PMID: 16941501 and internal data) (PM3_moderate). Computational tools predict no significant impact on splicing. Based on currently available information, the variant c.1101dup is classified as a pathogenic variant according to ACMG guidelines.

Oct 26, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 12 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as c.1059dupC (Arg354Glnfs*164). This variant has been observed in biallelic individuals affected with colorectal cancer and/or polyposis (PMID: 16941501, 24953332, 33130102). This variant has been identified in 1/250124 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

not provided Pathogenic:1

Jan 04, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This duplication of one nucleotide in MUTYH is denoted c.1101dupC at the cDNA level and p.Arg368GlnfsX164 (R368QfsX164) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GCCCCC[dupC]AGGG. The duplication causes a frameshift which changes an Arginine to a Glutamine at codon 368, and creates a premature stop codon at position 164 of the new reading frame. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 182 amino acids are no longer translated correctly and are replaced by 163 incorrect ones. This variant is predicted to cause loss of normal protein function through protein truncation. MUTYH Arg368GlnfsX164 has been reported in the compound heterozygous state with a pathogenic MUTYH variant in an individual with colorectal and breast cancer (Castillejo 2014). Based on the currently available information, we consider this duplication to be a likely pathogenic variant.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs768130289; hg19: chr1-45797417; COSMIC: COSV105895557; COSMIC: COSV105895557;