NM_001048174.2(MUTYH):c.849+3A>C AND Hereditary cancer-predisposing syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Feb 16, 2024
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:: RCV000129539.18

Allele description

NM_001048174.2(MUTYH):c.849+3A>C

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.849+3A>C

HGVS:

NC_000001.11:g.45332163T>G
NG_008189.1:g.13308A>C
NM_001048171.2:c.849+3A>C
NM_001048172.2:c.852+3A>C
NM_001048173.2:c.849+3A>C
NM_001048174.2:c.849+3A>CMANE SELECT
NM_001128425.2:c.933+3A>C
NM_001293190.2:c.894+3A>C
NM_001293191.2:c.882+3A>C
NM_001293192.2:c.573+3A>C
NM_001293195.2:c.849+3A>C
NM_001293196.2:c.573+3A>C
NM_001350650.2:c.504+3A>C
NM_001350651.2:c.504+3A>C
NM_012222.3:c.924+3A>C
LRG_220t1:c.933+3A>C
LRG_220:g.13308A>C
NC_000001.10:g.45797835T>G
NM_001048171.1:c.891+3A>C
NM_001128425.1:c.933+3A>C
NM_001128425.2:c.933+3A>C

Links:

dbSNP: rs587780751

NCBI 1000 Genomes Browser:

rs587780751

Molecular consequence:

NM_001048171.2:c.849+3A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001048172.2:c.852+3A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001048173.2:c.849+3A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001048174.2:c.849+3A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001128425.2:c.933+3A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001293190.2:c.894+3A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001293191.2:c.882+3A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001293192.2:c.573+3A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001293195.2:c.849+3A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001293196.2:c.573+3A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001350650.2:c.504+3A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001350651.2:c.504+3A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_012222.3:c.924+3A>C - intron variant - [Sequence Ontology: SO:0001627]

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

otos otospiralin [Danio rerio]
otos otospiralin [Danio rerio]
Gene ID:100535618

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
SCV000184317	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 16, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 19394335, 19732775, 22773231, 22865608, 27829682, 30604180, 32088803 Citation Link,
SCV000537683	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 12853198, 16616356, 18495334, 19732775, 20618354, 22773231, 22865608, 23108399, 27829682, 28135145, 29478780, 30564557, 33606809, 34506673, 35668106, 25741868
SCV004228050	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 5, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184317

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 16, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV000537683

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 11, 2023)

germline

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

SCV004228050

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 5, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH.

Jones N, Vogt S, Nielsen M, Christian D, Wark PA, Eccles D, Edwards E, Evans DG, Maher ER, Vasen HF, Hes FJ, Aretz S, Sampson JR.

Gastroenterology. 2009 Aug;137(2):489-94, 494.e1; quiz 725-6. doi: 10.1053/j.gastro.2009.04.047. Epub 2009 Apr 23.

PubMed [citation]

PMID:: 19394335

Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis.

Sutcliffe EG, Bartenbaker Thompson A, Stettner AR, Marshall ML, Roberts ME, Susswein LR, Wang Y, Klein RT, Hruska KS, Solomon BD.

Fam Cancer. 2019 Apr;18(2):203-209. doi: 10.1007/s10689-018-00116-2.

PubMed [citation]

PMID:: 30604180

See all PubMed Citations (19)

Details of each submission

From Ambry Genetics, SCV000184317.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The c.933+3A>C intronic alteration results from an A to C substitution 3 nucleotides after coding exon 10 of the MUTYH gene. Based on data from gnomAD, the C allele has an overall frequency of 0.007% (21/282792) total alleles studied. The highest observed frequency was 0.014% (18/129140) of European (non-Finnish) alleles. This alteration has been well described in the literature, and has been reported in both the homozygous and compound heterozygous state with other MUTYH alterations in multiple individuals with MUTYH-associated polyposis (Vogt, 2009; Urso, 2013; Ricci, 2017; Sutcliffe, 2019; Daans, 2020; Ambry internal data). This alteration has also been described as a founder mutation in the Northeastern Italian and German populations (Pin, 2013). Of note, this alteration is also designated as c.891+3A>C in published literature. This nucleotide position is poorly conserved in available vertebrate species. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration 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

From Color Diagnostics, LLC DBA Color Health, SCV000537683.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This variant causes an A to C nucleotide substitution at the +3 position of intron 10 of the MUTYH gene. Functional RNA studies have shown that this variant causes skipping of exon 10, resulting in a frameshift and premature stop codon (p.Gly264Trpfs*7) (PMID: 16616356, 22865608). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with MUTYH-associated polyposis as homozygous or in trans with another pathogenic variant (PMID: 12853198, 16616356, 18495334, 19732775, 20618354, 22773231, 22865608, 23108399, 27829682), colorectal cancer (PMID: 28135145, 29478780, 35668106), breast cancer (PMID: 30564557, 33606809), or pancreatic ductal adenocarcinoma (PMID: 34506673). This variant is considered a founder mutation in Western Europe (PMID: 22865608). This variant has been identified in 21/282792 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

From Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C., SCV004228050.1

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

#	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: Sep 16, 2024

ClinVar

Relating variation to medicine