1-45333452-C-T

Variant names:

• chr1-45333452-C-T
• rs748170941
• NM_001128425.2:c.309G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001128425.2(MUTYH):​c.309G>A​(p.Trp103*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000279 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: MUTYH NM_001128425.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.06
• 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-45333452-C-T is Pathogenic according to our data. Variant chr1-45333452-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 184976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	NM_001128425.2	MANE Plus Clinical	c.309G>A	p.Trp103*	stop_gained	Exon 3 of 16	NP_001121897.1
	MUTYH	NM_001048174.2	MANE Select	c.225G>A	p.Trp75*	stop_gained	Exon 3 of 16	NP_001041639.1
	MUTYH	NM_012222.3		c.300G>A	p.Trp100*	stop_gained	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.309G>A	p.Trp103*	stop_gained	Exon 3 of 16	ENSP00000518552.2
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.225G>A	p.Trp75*	stop_gained	Exon 3 of 16	ENSP00000407590.2
	MUTYH	ENST00000372098.7	TSL:1	c.300G>A	p.Trp100*	stop_gained	Exon 3 of 16	ENSP00000361170.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251488 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461890 Hom.: 0 Cov.: 35 AF XY: 0.0000358 AC XY: 26 AN XY: 727246

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: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1112010

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

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000127 Hom.: 0

Bravo AF: 0.0000151

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:8

Dec 11, 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.Trp103*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant is present in population databases (rs748170941, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with adenomatous polyposis (PMID: 15761860). This variant is also known as G267A (W89X). ClinVar contains an entry for this variant (Variation ID: 184976). For these reasons, this variant has been classified as Pathogenic.

Oct 30, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 3 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has been reported in individuals affected with colorectal polyposis (PMID: 15761860). This variant has been identified in 1/251488 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.

Apr 14, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Trp103X variant in MUTYH has been reported in the compound heterozygous state in 1 individual with MUTYH-associated polyposis (Aretz 2006, Vogt 2009, Sutcliffe 2019). It has been identified in 0.001% (1/113764) of chromosomes in Europeans by gnomAD (http://gnomad.broadinstitute.org).This variant has also been reported in ClinVar (Variation ID 184976). This nonsense variant leads to a premature termination codon at position 103, which is predicted to lead to a truncated or absent protein. Loss of function of the MUTYH gene is an established disease mechanism in autosomal recessive MUTYH-associated polyposis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MUTYH-associated polyposis. ACMG/AMP criteria applied: PVS1, PM2, PM3.

Dec 10, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Mar 15, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

May 24, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2023

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.309G>A (p.Trp103X) 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 251488 control chromosomes. c.309G>A has been reported in the literature in at least one individual affected with MUTYH-Associated Polyposis (Kairupan_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15761860). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as Pathogenic (n=6), Likely Pathogenic (n=2) and VUS (n=1. Based on the evidence outlined above, the variant was classified as pathogenic.

not provided Pathogenic:3

Jan 30, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 28152038, 34761457, 32885271, 15761860)

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MUTYH p.Trp103* variant was identified in 1 of 364 proband chromosomes (frequency: 0.003) from individuals or families with adenomatous polyposis (Kairupan 2005). The individual identified in this study was a compound heterozygote with a second pathogenic MUTYH mutation, p.Gly382Asp.The variant was also identified in dbSNP (ID: rs748170941) as "With Pathogenic allele ", ClinVar (classified as pathogenic by Invitae, Ambry Genetics and three other submitters; as likely pathogenic by Counsyl), and in the COGR database. The variant was not identified in Cosmic, or UMD-LSDB. The variant was identified in control databases in 1 of 246268 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European in 1 of 111716 chromosomes (freq: 0.000009), but not in other populations. The p.Trp103* variant leads to a premature stop codon at position 103, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

Nov 24, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 30, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W103* pathogenic mutation (also known as c.309G>A), located in coding exon 3 of the MUTYH gene, results from a G to A substitution at nucleotide position 309. This changes the amino acid from a tryptophan to a stop codon within coding exon 3. This alteration was reported in conjunction with an MUTYH founder mutation in an Australian woman with early-onset adenomatous polyposis (Kairupan CF et al. Int. J. Cancer, 2005 Aug;116:73-7). This alteration was also identified in an individual diagnosed with pancreatic cancer (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

May 04, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 3 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with colorectal polyposis in compound heterozygous state with a known pathogenic variant p.Gly382Asp (PMID: 15761860). This variant has been identified in 1/251488 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.

Gastric cancer;C3272841:Familial adenomatous polyposis 2 Pathogenic:1

Jan 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.1
Vest4		0.90
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs748170941; hg19: chr1-45799124;