chr1-45329315-TG-T

Position:

chr1-45329315-TG-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_001048174.2(MUTYH):c.1556delC(p.Ala519fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A519A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5

Conservation

PhyloP100: -1.05

Variant links:

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 links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00639 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-45329315-TG-T is Pathogenic according to our data. Variant chr1-45329315-TG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127843.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2 linkuse as main transcript	c.1556delC	p.Ala519fs	frameshift_variant	16/16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MUTYH	ENST00000456914.7 linkuse as main transcript	c.1556delC	p.Ala519fs	frameshift_variant	16/16	1	NM_001048174.2	ENSP00000407590.2	Q9UIF7-6
ENSG00000288208	ENST00000671898.1 linkuse as main transcript	n.*299delC		non_coding_transcript_exon_variant	21/21			ENSP00000499896.1	A0A5F9ZGZ0
ENSG00000288208	ENST00000671898 linkuse as main transcript	n.*299delC		3_prime_UTR_variant	15/15			ENSP00000499896.1	A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251494

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135920

show subpopulations

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:

0.0000462

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

show subpopulations

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

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:

0.000188

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:1Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 15, 2023	This sequence change results in a frameshift in the MUTYH gene (p.Ala547Glufs*24). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acid(s) of the MUTYH protein and extend the protein by 20 additional amino acid residues. This variant is present in population databases (rs587780086, gnomAD 0.004%). This frameshift has been observed in individual(s) with MUTYH-associated polyposis (PMID: 34704405; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 127843). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 26, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 20, 2015	- -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 26, 2023	The c.1640delC variant, located in coding exon 16 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 1640, causing a translational frameshift with a predicted alternate stop codon (p.A547Efs*24). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of MUTYH, is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 20 amino acids. This variant has been detected in a patient diagnosed with 1-10 adenomas before age 61 (Baert-Desurmont S et al. Eur J Hum Genet. 2018 Nov;26(11):1597-1602). This alteration has also been detected in a biallelic state in multiple patients with polyposis (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 27, 2019	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2014

This variant is denoted MUTYH c.1640delC at the cDNA level and p.Ala547GlufsX24 (A547EfsX24) at the protein level. The normal sequence, with the base that is deleted in brackets, is AGTG[C]AGCC. The deletion causes a frameshift in codon 547, which changes an Alanine to a Glutamic Acid, resulting in in the loss of a native stop codon, replacing the last 3 amino acids and likely causing the protein to be extended by 20 more amino acids on the new reading frame. MUTYH Ala547GlufsX24 has not, to our knowledge, been published in the literature as pathogenic or benign. This variant has not been observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Despite the frameshift nature of this variant, its location at the end of the protein might not cause a deleterious effect on protein structure or function. Therefore, with the data currently available, we consider MUTYH Ala547GlufsX24 to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over