NM_001048174.2(MUTYH):c.379-1G>A AND Familial adenomatous polyposis 2

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Oct 23, 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:: RCV000553473.9

Allele description [Variation Report for NM_001048174.2(MUTYH):c.379-1G>A]

NM_001048174.2(MUTYH):c.379-1G>A

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.379-1G>A

HGVS:

NC_000001.11:g.45332960C>T
NG_008189.1:g.12511G>A
NM_001048171.2:c.379-1G>A
NM_001048172.2:c.382-1G>A
NM_001048173.2:c.379-1G>A
NM_001048174.2:c.379-1G>AMANE SELECT
NM_001128425.2:c.463-1G>A
NM_001293190.2:c.424-1G>A
NM_001293191.2:c.412-1G>A
NM_001293192.2:c.103-1G>A
NM_001293195.2:c.379-1G>A
NM_001293196.2:c.103-1G>A
NM_001350650.2:c.34-1G>A
NM_001350651.2:c.34-1G>A
NM_001407069.1:c.454-126G>A
NM_001407070.1:c.379-1G>A
NM_001407071.1:c.382-1G>A
NM_001407072.1:c.379-1G>A
NM_001407073.1:c.421-126G>A
NM_001407075.1:c.295-1G>A
NM_001407077.1:c.412-1G>A
NM_001407078.1:c.382-1G>A
NM_001407079.1:c.382-126G>A
NM_001407080.1:c.379-126G>A
NM_001407081.1:c.379-1G>A
NM_001407082.1:c.34-1G>A
NM_001407083.1:c.421-1G>A
NM_001407085.1:c.421-1G>A
NM_001407086.1:c.382-1G>A
NM_001407087.1:c.400-1G>A
NM_001407088.1:c.379-1G>A
NM_001407089.1:c.379-1G>A
NM_001407091.1:c.103-1G>A
NM_012222.3:c.454-1G>A
LRG_220t1:c.463-1G>A
LRG_220:g.12511G>A
NC_000001.10:g.45798632C>T
NM_001048174.2:c.379-1G>A
NM_001128425.1:c.463-1G>A

Links:

dbSNP: rs1057520660

NCBI 1000 Genomes Browser:

rs1057520660

Molecular consequence:

NM_001407069.1:c.454-126G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001407073.1:c.421-126G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001407079.1:c.382-126G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001407080.1:c.379-126G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001048171.2:c.379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001048172.2:c.382-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001048173.2:c.379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001048174.2:c.379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001128425.2:c.463-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001293190.2:c.424-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001293191.2:c.412-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001293192.2:c.103-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001293195.2:c.379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001293196.2:c.103-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001350650.2:c.34-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001350651.2:c.34-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407070.1:c.379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407071.1:c.382-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407072.1:c.379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407075.1:c.295-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407077.1:c.412-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407078.1:c.382-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407081.1:c.379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407082.1:c.34-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407083.1:c.421-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407085.1:c.421-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407086.1:c.382-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407087.1:c.400-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407088.1:c.379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407089.1:c.379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407091.1:c.103-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_012222.3:c.454-1G>A - 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
SCV000639325	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 23, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16557584, 19732775, 28492532
SCV004826731	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Apr 28, 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

SCV000639325

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 23, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004826731

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Apr 28, 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

MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype.

Aretz S, Uhlhaas S, Goergens H, Siberg K, Vogel M, Pagenstecher C, Mangold E, Caspari R, Propping P, Friedl W.

Int J Cancer. 2006 Aug 15;119(4):807-14.

PubMed [citation]

PMID:: 16557584

Expanded extracolonic tumor spectrum in MUTYH-associated polyposis.

Vogt S, Jones N, Christian D, Engel C, Nielsen M, Kaufmann A, Steinke V, Vasen HF, Propping P, Sampson JR, Hes FJ, Aretz S.

Gastroenterology. 2009 Dec;137(6):1976-85.e1-10. doi: 10.1053/j.gastro.2009.08.052. Epub 2009 Sep 2.

PubMed [citation]

PMID:: 19732775

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000639325.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change affects an acceptor splice site in intron 5 of the MUTYH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 1 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with MUTYH-associated polyposis (PMID: 16557584, 19732775; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 379599). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 6 (Invitae). 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.

#	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, SCV004826731.1

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

Description

This variant causes a G to A nucleotide substitution at the -1 position of intron 5 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-related disorders in the literature. This variant has not been identified 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: Sep 29, 2024

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