NM_000251.3(MSH2):c.2459-1G>C AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 30, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000698818.6

Allele description [Variation Report for NM_000251.3(MSH2):c.2459-1G>C]

NM_000251.3(MSH2):c.2459-1G>C

Gene:

MSH2:mutS homolog 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.2459-1G>C

HGVS:

NC_000002.12:g.47480695G>C
NG_007110.2:g.82572G>C
NM_000251.1:c.2459-1G>C
NM_000251.3:c.2459-1G>CMANE SELECT
NM_001258281.1:c.2261-1G>C
NM_001406631.1:c.2459-1G>C
NM_001406632.1:c.2459-1G>C
NM_001406633.1:c.2459-1G>C
NM_001406634.1:c.2459-1G>C
NM_001406635.1:c.2459-1G>C
NM_001406636.1:c.2426-1G>C
NM_001406637.1:c.2459-1G>C
NM_001406638.1:c.2498-1G>C
NM_001406639.1:c.2459-1G>C
NM_001406640.1:c.2459-1G>C
NM_001406641.1:c.2459-1G>C
NM_001406642.1:c.2459-1G>C
NM_001406643.1:c.2459-1G>C
NM_001406644.1:c.2459-1G>C
NM_001406645.1:c.2459-1G>C
NM_001406646.1:c.2459-1G>C
NM_001406647.1:c.2309-1G>C
NM_001406648.1:c.2459-1G>C
NM_001406649.1:c.2309-1G>C
NM_001406650.1:c.2309-1G>C
NM_001406651.1:c.2309-1G>C
NM_001406652.1:c.2309-1G>C
NM_001406653.1:c.2399-1G>C
NM_001406654.1:c.2039-1G>C
NM_001406656.1:c.1562-1G>C
NM_001406658.1:c.1103-1G>C
NM_001406659.1:c.1103-1G>C
NM_001406660.1:c.1103-1G>C
NM_001406661.1:c.1103-1G>C
NM_001406662.1:c.1103-1G>C
NM_001406669.1:c.1103-1G>C
NM_001406674.1:c.2459-1G>C
LRG_218t1:c.2459-1G>C
LRG_218:g.82572G>C
NC_000002.11:g.47707834G>C
NM_000251.2:c.2459-1G>C

Links:

dbSNP: rs1060501991

NCBI 1000 Genomes Browser:

rs1060501991

Molecular consequence:

NM_000251.3:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001258281.1:c.2261-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406631.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406632.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406633.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406634.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406635.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406636.1:c.2426-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406637.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406638.1:c.2498-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406639.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406640.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406641.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406642.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406643.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406644.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406645.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406646.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406647.1:c.2309-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406648.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406649.1:c.2309-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406650.1:c.2309-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406651.1:c.2309-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406652.1:c.2309-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406653.1:c.2399-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406654.1:c.2039-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406656.1:c.1562-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406658.1:c.1103-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406659.1:c.1103-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406660.1:c.1103-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406661.1:c.1103-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406662.1:c.1103-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406669.1:c.1103-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406674.1:c.2459-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000827506	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 30, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 15849733, 24362816, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000827506

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 30, 2019)

germline

clinical testing

PubMed (4)
[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

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

Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer.

Mangold E, Pagenstecher C, Friedl W, Mathiak M, Buettner R, Engel C, Loeffler M, Holinski-Feder E, Müller-Koch Y, Keller G, Schackert HK, Krüger S, Goecke T, Moeslein G, Kloor M, Gebert J, Kunstmann E, Schulmann K, Rüschoff J, Propping P.

Int J Cancer. 2005 Sep 20;116(5):692-702.

PubMed [citation]

PMID:: 15849733

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000827506.6

#	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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. This sequence change affects an acceptor splice site in intron 14 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

#	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 29, 2024

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