1-45333452-C-T

Position:

• chr1-45333452-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001048174.2(MUTYH):​c.225G>A​(p.Trp75Ter) 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 Likely 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_001048174.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.06

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 1-45333452-C-T is Pathogenic according to our data. Variant chr1-45333452-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 184976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.309G>A	p.Trp103Ter	stop_gained	3/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.225G>A	p.Trp75Ter	stop_gained	3/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.309G>A	p.Trp103Ter	stop_gained	3/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.225G>A	p.Trp75Ter	stop_gained	3/16	1	NM_001048174.2	A1

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

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251488 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000278 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/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 30, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 14, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 24, 2019	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Dec 10, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	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. -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2018	This pathogenic variant is denoted MUTYH c.309G>A at the cDNA level, p.Trp103Ter (W103X) at theprotein level, and results in the change of a Tryptophan to Nonsense (TGG>TGA). This variant, also published asMUTYH c.267G>A (p.W89X) using alternate nomenclature, has been observed in at least one individual with a historyof polyposis who was also found to harbor a known pathogenic MUTYH variant (Kairupan 2005). MUTYH Trp103Terwas not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The1000 Genomes Consortium 2015, Lek 2016). Based on currently available evidence, we consider this variant to bepathogenic. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenicvariants on opposite chromosomes in MUTYH. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 24, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 04, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 10, 2021	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. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;D;D;D;D
Vest4		0.90
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs748170941; hg19: chr1-45799124;