1-45332574-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001048174.2(MUTYH):c.606G>A(p.Gln202=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000248 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 splice_region, synonymous

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.83

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 1-45332574-C-T is Pathogenic according to our data. Variant chr1-45332574-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 481804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45332574-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2 linkuse as main transcript	c.690G>A	p.Gln230=	splice_region_variant, synonymous_variant	8/16	ENST00000710952.2
MUTYH	NM_001048174.2 linkuse as main transcript	c.606G>A	p.Gln202=	splice_region_variant, synonymous_variant	8/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2 linkuse as main transcript	c.690G>A	p.Gln230=	splice_region_variant, synonymous_variant	8/16		NM_001128425.2
MUTYH	ENST00000456914.7 linkuse as main transcript	c.606G>A	p.Gln202=	splice_region_variant, synonymous_variant	8/16	1	NM_001048174.2	A1	Q9UIF7-6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251322

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135874

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:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727214

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

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:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 29, 2024	The c.690G>A pathogenic mutation (also known as p.Q230Q), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 690. This nucleotide substitution does not change the glutamine at codon 230. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This variant has been reported as compound heterozygous in individuals with colorectal polyposis; furthermore, this mutation has been shown to result in aberrant splicing with exon 8 skipping by RNA studies (Ambry internal data; Vogt S et al. Gastroenterology 2009 Dec; 137(6):1976-85.e1-10; Dallosso AR et al. Gut 2008 Sep; 57(9):1252-5). Of note, this mutation is also designated as c.681G>A in the published literature. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 28, 2023	This synonymous variant does not change the amino acid sequence of the MUTYH protein, but it causes a G to A substitution at the last nucleotide position of exon 8 of the MUTYH gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An RNA study has shown that this variant (also known as c.681G>A in the literature) causes skipping of exon 8 in the MUTYH transcript (PMID: 18515411). This variant has been reported in the compound heterozygous state in individuals affected with MUTYH-associated polyposis (PMID:18515411, 19032956, 19732775, 25559809). This variant has also been identified in 1/251322 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 Likely Pathogenic. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate abnormal splicing resulting in skipping of exon 8 (Dallosso et al., 2008); In silico analysis supports that this variant may damage or destroy the splice donor site and impact gene splicing; This variant is associated with the following publications: (PMID: 19032956, 19732775, 19394335, 23212176, 25525159, 18515411, 25559809, 34704405) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 27, 2018	- -

Familial adenomatous polyposis 2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This synonymous variant does not change the amino acid sequence of the MUTYH protein, but it causes a G to A substitution at the last nucleotide position of exon 8 of the MUTYH gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An RNA study has shown that this variant (also known as c.681G>A in the literature) causes skipping of exon 8 in the MUTYH transcript (PMID: 18515411). This variant has been reported in the compound heterozygous state in individuals affected with MUTYH-associated polyposis (PMID:18515411, 19032956, 19732775, 25559809). This variant has also been identified in 1/251322 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 Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2023	This sequence change affects codon 230 of the MUTYH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MUTYH protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs199989617, gnomAD 0.0009%). This variant has been observed in individual(s) with MUTYH-associated polyposis (PMID: 19732775, 25559809). 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.681G>A. ClinVar contains an entry for this variant (Variation ID: 481804). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 18515411). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

Cadd

Benign

Dann

Benign

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.94

Position offset: 0

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