NM_001048174.2(MUTYH):c.228C>A (p.Tyr76Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 14, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000163049.20

Allele description [Variation Report for NM_001048174.2(MUTYH):c.228C>A (p.Tyr76Ter)]

NM_001048174.2(MUTYH):c.228C>A (p.Tyr76Ter)

Gene:

MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_001048174.2(MUTYH):c.228C>A (p.Tyr76Ter)

HGVS:

NC_000001.11:g.45333449G>T
NG_008189.1:g.12022C>A
NM_001048171.2:c.228C>A
NM_001048172.2:c.231C>A
NM_001048173.2:c.228C>A
NM_001048174.2:c.228C>AMANE SELECT
NM_001128425.2:c.312C>A
NM_001293190.2:c.273C>A
NM_001293191.2:c.261C>A
NM_001293192.2:c.-49C>A
NM_001293195.2:c.228C>A
NM_001293196.2:c.-49C>A
NM_001350650.2:c.-44C>A
NM_001350651.2:c.-44C>A
NM_012222.3:c.303C>A
NP_001041636.1:p.Tyr90Ter
NP_001041636.2:p.Tyr76Ter
NP_001041637.1:p.Tyr77Ter
NP_001041638.1:p.Tyr76Ter
NP_001041639.1:p.Tyr76Ter
NP_001121897.1:p.Tyr104Ter
NP_001121897.1:p.Tyr104Ter
NP_001280119.1:p.Tyr91Ter
NP_001280120.1:p.Tyr87Ter
NP_001280124.1:p.Tyr76Ter
NP_036354.1:p.Tyr101Ter
LRG_220t1:c.312C>A
LRG_220:g.12022C>A
LRG_220p1:p.Tyr104Ter
NC_000001.10:g.45799121G>T
NM_001048171.1:c.270C>A
NM_001128425.1:c.312C>A
NR_146882.2:n.456C>A
NR_146883.2:n.379C>A
p.Tyr104*
p.Y104*

Protein change:

Y101*; TYR90TER

Links:

OMIM: 604933.0004; dbSNP: rs121908380

NCBI 1000 Genomes Browser:

rs121908380

Molecular consequence:

NM_001293192.2:c.-49C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293196.2:c.-49C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350650.2:c.-44C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350651.2:c.-44C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NR_146882.2:n.456C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.379C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001048171.2:c.228C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001048172.2:c.231C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001048173.2:c.228C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001048174.2:c.228C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001128425.2:c.312C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001293190.2:c.273C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001293191.2:c.261C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001293195.2:c.228C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_012222.3:c.303C>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Clear Turn Off Turn On

LOC130063261 [Homo sapiens]
LOC130063261 [Homo sapiens]
Gene ID:130063261

Gene

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000213540	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 16, 2021)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12393807, 18091433, 18534194, 19032956, 19732775, 22976915, 27705013, 27829682, 28152038 Citation Link,
SCV000685609	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 14, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 12393807, 17273161, 17369389, 18091433, 18534194, 18564191, 19279422, 19732775, 22976915, 24444654, 27705013, 27829682, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000213540

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 16, 2021)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV000685609

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 14, 2023)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis.

Nielsen M, Joerink-van de Beld MC, Jones N, Vogt S, Tops CM, Vasen HF, Sampson JR, Aretz S, Hes FJ.

Gastroenterology. 2009 Feb;136(2):471-6. doi: 10.1053/j.gastro.2008.10.056. Epub 2008 Oct 30.

PubMed [citation]

PMID:: 19032956

Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels.

LaDuca H, Farwell KD, Vuong H, Lu HM, Mu W, Shahmirzadi L, Tang S, Chen J, Bhide S, Chao EC.

PLoS One. 2017;12(2):e0170843. doi: 10.1371/journal.pone.0170843.

PubMed [citation]

PMID:: 28152038
PMCID:: PMC5289469

See all PubMed Citations (15)

Details of each submission

From Ambry Genetics, SCV000213540.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.Y104* pathogenic mutation (also known as c.312C>A), located in coding exon 3 of the MUTYH gene, results from a C to A substitution at nucleotide position 312. This changes the amino acid from a tyrosine to a stop codon within exon 3. This alteration has been detected in the homozygous state in multiple colorectal polyposis families and has been shown to abolish normal MUTYH protein function (Jones S et al. Hum. Mol. Genet. 2002 Nov;11:2961-7; Ali M et al. Gastroenterology. 2008 Aug;135:499-507; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85). In one study, the p.Y104* pathogenic mutation was reported in the homozygous state in one Italian individual diagnosed with MUTYH-associated polyposis (MAP) and in the compound heterozygous state in five other Italian MAP patients (Ricci MT et al. J. Hum. Genet. 2017 Feb;62:309-315). This alteration has also been identified in either the compound heterozygous or homozygous state in numerous other probands diagnosed with adenomatous polyposis (Ambry internal data; Marabelli M et al. Genet Test Mol Biomarkers, 2016 12;20:777-785; de Leon MP et al. Tech Coloproctol, 2013 Feb;17:79-87; Cattaneo F et al. Genet Med, 2007 Dec;9:836-41). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000685609.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This variant changes 1 nucleotide in exon 3 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant resulted in no detectable glycolysase activity or DNA binding in protein extracts (PMID: 18534194). This variant has been reported in biallelic individuals affected with MUTYH-associated polyposis (PMID: 12393807, 17273161, 17369389, 18091433, 18564191, 19279422, 19732775, 22976915, 24444654, 27705013, 27829682). This variant has been identified in 31/282862 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

ClinVar

Relating variation to medicine