NM_001048174.2(MUTYH):c.-6-2A>G AND Familial adenomatous polyposis 2

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Dec 13, 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:: RCV000687716.9

Allele description [Variation Report for NM_001048174.2(MUTYH):c.-6-2A>G]

NM_001048174.2(MUTYH):c.-6-2A>G

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.-6-2A>G

HGVS:

NC_000001.11:g.45334513T>C
NG_008189.1:g.10958A>G
NM_001048171.2:c.-6-2A>G
NM_001048172.2:c.-6-2A>G
NM_001048173.2:c.-6-2A>G
NM_001048174.2:c.-6-2A>GMANE SELECT
NM_001128425.2:c.37-2A>G
NM_001293190.2:c.37-2A>G
NM_001293191.2:c.-6-2A>G
NM_001293192.2:c.-218-2A>G
NM_001293195.2:c.-6-2A>G
NM_001293196.2:c.-218-2A>G
NM_001350650.2:c.-277-2A>G
NM_001350651.2:c.-213-2A>G
NM_001407069.1:c.37-2A>G
NM_001407070.1:c.-6-2A>G
NM_001407071.1:c.-6-2A>G
NM_001407072.1:c.-6-2A>G
NM_001407073.1:c.37-2A>G
NM_001407075.1:c.-162-2A>G
NM_001407077.1:c.-6-2A>G
NM_001407078.1:c.-6-2A>G
NM_001407079.1:c.-6-2A>G
NM_001407080.1:c.-6-2A>G
NM_001407081.1:c.-6-2A>G
NM_001407082.1:c.-213-2A>G
NM_001407083.1:c.-6-2A>G
NM_001407085.1:c.-6-2A>G
NM_001407086.1:c.-6-2A>G
NM_001407087.1:c.13-2A>G
NM_001407088.1:c.-6-2A>G
NM_001407089.1:c.-6-2A>G
NM_001407091.1:c.-218-2A>G
NM_012222.3:c.37-2A>G
LRG_220t1:c.37-2A>G
LRG_220:g.10958A>G
NC_000001.10:g.45800185T>C
NM_001128425.1:c.37-2A>G

Links:

dbSNP: rs1383826978

NCBI 1000 Genomes Browser:

rs1383826978

Molecular consequence:

NM_001048171.2:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001048172.2:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001048173.2:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001048174.2:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001128425.2:c.37-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001293190.2:c.37-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001293191.2:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001293192.2:c.-218-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001293195.2:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001293196.2:c.-218-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001350650.2:c.-277-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001350651.2:c.-213-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407069.1:c.37-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407070.1:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407071.1:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407072.1:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407073.1:c.37-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407075.1:c.-162-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407077.1:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407078.1:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407079.1:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407080.1:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407081.1:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407082.1:c.-213-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407083.1:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407085.1:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407086.1:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407087.1:c.13-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407088.1:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407089.1:c.-6-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407091.1:c.-218-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_012222.3:c.37-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: Familial adenomatous polyposis 2
Synonyms:: COLORECTAL ADENOMATOUS POLYPOSIS, AUTOSOMAL RECESSIVE; ADENOMAS, MULTIPLE COLORECTAL, AUTOSOMAL RECESSIVE; MYH-associated polyposis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012041; MedGen: C3272841; Orphanet: 220460; OMIM: 608456

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000815301	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 19, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 18534194, 20663686, 28492532
SCV004842747	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Dec 13, 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

SCV000815301

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 19, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004842747

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Dec 13, 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	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Characterization of mutant MUTYH proteins associated with familial colorectal cancer.

Ali M, Kim H, Cleary S, Cupples C, Gallinger S, Bristow R.

Gastroenterology. 2008 Aug;135(2):499-507. doi: 10.1053/j.gastro.2008.04.035. Epub 2008 May 7.

PubMed [citation]

PMID:: 18534194
PMCID:: PMC2761659

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000815301.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 560804). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 1 of the MUTYH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686).

#	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 All of Us Research Program, National Institutes of Health, SCV004842747.1

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

Description

This variant causes an A to G nucleotide substitution at the -2 position of intron 1 of the MUTYH gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with MUTYH-associated disorders in the literature. This variant has been identified in 1/251466 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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