rs587780082

Positions:

• chr1-45331835-G-A

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.928C>T​(p.Gln310Ter) 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 (★★). 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 1.91

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 1-45331835-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/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1012C>T	p.Gln338Ter	stop_gained	12/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.928C>T	p.Gln310Ter	stop_gained	12/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.1012C>T	p.Gln338Ter	stop_gained	12/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.928C>T	p.Gln310Ter	stop_gained	12/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152246 Hom.: 0 Cov.: 33

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: 19 AN: 232530 Hom.: 0 AF XY: 0.0000634 AC XY: 8 AN XY: 126222

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: 31 AN: 1451788 Hom.: 0 Cov.: 36 AF XY: 0.0000236 AC XY: 17 AN XY: 721312

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: 5 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

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.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000989 AC: 12

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2019	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. -
Pathogenic, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Oct 01, 2016	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. -
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.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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	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. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 30, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 14, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 31, 2021	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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.20	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;N;N;N;N
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

Other links and lift over

dbSNP: rs587780082; hg19: chr1-45797507;