chr1-45331745-TG-T

Position:

• chr1-45331745-TG-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.1017del​(p.Arg340GlyfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MUTYH NM_001048174.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.280

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 1-45331745-TG-T is Pathogenic according to our data. Variant chr1-45331745-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 491999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331745-TG-T is described in Lovd as [Likely_pathogenic]. Variant chr1-45331745-TG-T is described in Lovd as [Likely_pathogenic]. Variant chr1-45331745-TG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1101del	p.Arg368GlyfsTer40	frameshift_variant	12/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.1017del	p.Arg340GlyfsTer40	frameshift_variant	12/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.1101del	p.Arg368GlyfsTer40	frameshift_variant	12/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.1017del	p.Arg340GlyfsTer40	frameshift_variant	12/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250124 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135574

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461796 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 727200

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: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change creates a premature translational stop signal (p.Arg368Glyfs*40) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with MUTYH-associated polyposis (PMID: 18515411, 19732775). This variant is also known as c.1092delC. ClinVar contains an entry for this variant (Variation ID: 491999). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Mar 09, 2023	This variant deletes 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 has been reported in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 18515411, 19032956, 19732775, 20687945). In one of these affected individuals, this variant has been determined to be compound heterozygous with another pathogenic variant in the same gene (PMID: 19732775), indicating that this variant contributes to MUTYH-associated polyposis in an autosomal recessive manner. 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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 15, 2022	The c.1101delC pathogenic mutation, located in coding exon 12 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 1101, causing a translational frameshift with a predicted alternate stop codon (p.R368Gfs*40). This alteration has been previously identified in conjunction with another pathogenic MUTYH mutation in 2 unrelated individuals with colorectal adenomas and/or colorectal cancer (Dallosso AR et al. Gut, 2008 Sep;57:1252-5; Vogt S et al. Gastroenterology, 2009 Dec;137:1976-85.e1-10). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 01, 2023	This variant deletes 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 has been reported in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 18515411, 19032956, 19732775, 20687945). In one of these affected individuals, this variant has been determined to be compound heterozygous with another pathogenic variant in the same gene (PMID: 19732775), indicating that this variant contributes to MUTYH-associated polyposis in an autosomal recessive manner. 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. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs768130289; hg19: chr1-45797417;