rs587780082

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001048174.2(MUTYH):c.928C>T(p.Gln310*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,604,034 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Q310Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 1.91

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 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 1-45331835-G-A is Pathogenic according to our data. Variant chr1-45331835-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 127835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331835-G-A is described in Lovd as [Pathogenic]. Variant chr1-45331835-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.928C>T	p.Gln310*	stop_gained	Exon 12 of 16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 link	c.928C>T	p.Gln310*	stop_gained	Exon 12 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1516C>T		non_coding_transcript_exon_variant	Exon 16 of 21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000817

AC:

AN:

232530

Hom.:

AF XY:

0.0000634

AC XY:

AN XY:

126222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000460

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000341

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000193

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.0000214

AC:

AN:

1451788

Hom.:

Cov.:

AF XY:

0.0000236

AC XY:

AN XY:

721312

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000440

Gnomad4 ASJ exome

AF:

0.0000388

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000723

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000989

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Jan 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 04, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MUTYH c.1012C>T (p.Gln338*) variant has been reported in the published literature in individuals affected with MUTYH-associated polyposis (MAP) (PMID: 12853198 (2003), 19732775 (2009), 24470512 (2014), 34704405 (2021)), colorectal neoplasias (PMID: 27829682 (2016)), and breast cancer (PMID: 33471991, see also LOVD (http://databases.lovd.nl/shared)). This variant has also been reported to affect MUTYH protein expression and DNA glycosylase activity (PMID: 20848659 (2009)). The frequency of this variant in the general population, 0.00045 (15/33490 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Dec 30, 2016

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2022

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; Observed with a pathogenic variant on the opposite allele (in trans) in individuals with colorectal cancer and/or polyps the published literature (Sampson et al., 2003; Aretz et al., 2006; Bouguen et al., 2007; Cattaneo et al., 2008; Vogt et al., 2009; Ricci et al., 2017); Published functional studies demonstrate a damaging effect: severely defective DNA glycosylase activity (Goto et al., 2010); Also known as c.970C>T p.(Gln324Ter) and c.928C>T p.(Gln310Ter); This variant is associated with the following publications: (PMID: 12853198, 25525159, 19032956, 31589614, 16557584, 17674103, 18091433, 19732775, 27829682, 26556299, 31203172, 20848659) -

Familial adenomatous polyposis 2

Pathogenic:5

Dec 28, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 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.Gln338*) 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 (rs587780082, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with MUTYH-associated polyposis (MAP) (PMID: 2084865, 12853198, 16557584, 19732775, 24470512). This variant is also known as Q310X and Q324X. ClinVar contains an entry for this variant (Variation ID: 127835). For these reasons, this variant has been classified as Pathogenic. -

Jul 10, 2019

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.1012C>T (p.Gln338X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.2e-05 in 232530 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (8.2e-05 vs 0.0046), allowing no conclusion about variant significance. c.1012C>T has been reported in the literature in multiple individuals affected with MUTYH-associated Polyposis (Sampson_2003, Vogt_2009, Ricci_2017). These data indicate that the variant is very likely to be associated with disease. A functional study, GOTO_2010 reports the variant severely impairs adenine DNA glycosylase activity. Six ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 01, 2016

CSER _CC_NCGL, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 53 year old male diagnosed with colon cancer at age 47. Patient is compound heterozygous for a second pathogenic variant in MUTYH. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

Sep 23, 2024

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 12 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study reported that this variant was severely defective for DNA glycosylase activity (PMID: 20848659). To our knowledge, this variant has been reported in individuals affected with MUTYH-associated polyposis (PMID: 12853198, 16557584, 17674103, 17949294, 19032956, 19394335, 19732775, 24470512, 26556299, 27829682). This variant has been identified in 20/263922 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

Dec 14, 2022

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 12 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study reported that this variant was severely defective for DNA glycosylase activity (PMID: 20848659). This variant has been reported in individuals affected with MUTYH-associated polyposis (PMID: 12853198, 16557584, 17674103, 17949294, 19032956, 19394335, 19732775, 24470512, 26556299, 27829682, 34704405). This variant has been identified in 20/263922 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. -

Dec 31, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q338* pathogenic mutation (also known as c.1012C>T), located in coding exon 12 of the MUTYH gene, results from a C to T substitution at nucleotide position 1012. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration has been described in several individuals with attenuated polyposis and/or colon cancer (Sampson JR et al. Lancet. 2003 Jul;362:39-41; Aretz S et al. Int. J. Cancer. 2006 Aug;119:807-14; Olschwang S et al. Genet. Test. 2007;11:315-20; Bouguen G et al. Dis. Colon Rectum. 2007 Oct;50:1612-7; Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6; Jones N et al. Gastroenterology. 2009 Aug;137:489-94, 494.e1; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85.e1-10; Guarinos C et al. Clin. Cancer Res. 2014 Mar;20:1158-68). The glycosylation function of the p.Q338* mutant MUTYH was classified as extremely impaired in one study measuring DNA glycosylase activity on adenine mispaired with 8-hydroxyguanine (Goto M et al. Hum. Mutat. 2010 Nov;31:E1861-74). Of note, p.Q338* has also been referred to as p.Q324X and p.Q310* in the literature. 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. -

Gastric cancer;C3272841:Familial adenomatous polyposis 2

Pathogenic:1

Jan 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.20

Vest4

0.94

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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