NM_000251.3(MSH2):c.2635-1G>C AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 11, 2024
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:: RCV000491490.4

Allele description [Variation Report for NM_000251.3(MSH2):c.2635-1G>C]

NM_000251.3(MSH2):c.2635-1G>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.2635-1G>C

HGVS:

NC_000002.12:g.47482778G>C
NG_007110.2:g.84655G>C
NM_000251.3:c.2635-1G>CMANE SELECT
NM_001258281.1:c.2437-1G>C
NM_001406631.1:c.2634+1907G>C
NM_001406632.1:c.2634+1907G>C
NM_001406633.1:c.2634+1907G>C
NM_001406634.1:c.2634+1907G>C
NM_001406635.1:c.2634+1907G>C
NM_001406636.1:c.2601+1907G>C
NM_001406637.1:c.2634+1907G>C
NM_001406638.1:c.2674-1G>C
NM_001406639.1:c.2634+1907G>C
NM_001406640.1:c.2634+1907G>C
NM_001406641.1:c.2635-1G>C
NM_001406642.1:c.2634+1907G>C
NM_001406643.1:c.2634+1907G>C
NM_001406644.1:c.2634+1907G>C
NM_001406645.1:c.2634+1907G>C
NM_001406646.1:c.2634+1907G>C
NM_001406647.1:c.2484+1907G>C
NM_001406649.1:c.2485-1G>C
NM_001406650.1:c.2485-1G>C
NM_001406651.1:c.2484+1907G>C
NM_001406652.1:c.2484+1907G>C
NM_001406654.1:c.2214+1907G>C
NM_001406656.1:c.1737+1907G>C
NM_001406658.1:c.1279-1G>C
NM_001406659.1:c.1279-1G>C
NM_001406660.1:c.1279-1G>C
NM_001406661.1:c.1279-1G>C
NM_001406662.1:c.1279-1G>C
NM_001406669.1:c.1278+1907G>C
NM_001406674.1:c.2634+1907G>C
LRG_218t1:c.2635-1G>C
LRG_218:g.84655G>C
NC_000002.11:g.47709917G>C
NM_000251.1:c.2635-1G>C
NM_000251.2:c.2635-1G>C

Links:

dbSNP: rs267608020

NCBI 1000 Genomes Browser:

rs267608020

Molecular consequence:

NM_001406631.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406632.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406633.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406634.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406635.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406636.1:c.2601+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406637.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406639.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406640.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406642.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406643.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406644.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406645.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406646.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406647.1:c.2484+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406651.1:c.2484+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406652.1:c.2484+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406654.1:c.2214+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406656.1:c.1737+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406669.1:c.1278+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406674.1:c.2634+1907G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000251.3:c.2635-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001258281.1:c.2437-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406638.1:c.2674-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406641.1:c.2635-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406649.1:c.2485-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406650.1:c.2485-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406658.1:c.1279-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406659.1:c.1279-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406660.1:c.1279-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406661.1:c.1279-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406662.1:c.1279-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000580615	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 11, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12624141, 15849733 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000580615

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 11, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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

Cancer risk in 348 French MSH2 or MLH1 gene carriers.

Parc Y, Boisson C, Thomas G, Olschwang S.

J Med Genet. 2003 Mar;40(3):208-13. No abstract available.

PubMed [citation]

PMID:: 12624141
PMCID:: PMC1735402

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

Details of each submission

From Ambry Genetics, SCV000580615.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.2635-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 16 of the MSH2 gene. This mutation (designated as IVS15-1g>c) was identified in a French family with HNPCC (Parc Y et al. J. Med. Genet. 2003 Mar;40:208-13) and in a patient whose tumor demonstrated absent MSH2 and MSH6 staining by IHC analysis (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified 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

Last Updated: Sep 29, 2024

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