NM_000251.3(MSH2):c.2006-1G>C AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Feb 27, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000251.3(MSH2):c.2006-1G>C]


MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000002.12:g.47476366G>C
  • NG_007110.2:g.78243G>C
  • NM_000251.3:c.2006-1G>CMANE SELECT
  • NM_001258281.1:c.1808-1G>C
  • LRG_218t1:c.2006-1G>C
  • LRG_218:g.78243G>C
  • NC_000002.11:g.47703505G>C
  • NM_000251.1:c.2006-1G>C
  • NM_000251.2:c.2006-1G>C
dbSNP: rs267607988
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000251.3:c.2006-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258281.1:c.1808-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]


Hereditary cancer-predisposing syndrome
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000580477Ambry Geneticscriteria provided, single submitter
(Feb 27, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



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]

Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal cancer.

Stormorken AT, Bowitz-Lothe IM, Norèn T, Kure E, Aase S, Wijnen J, Apold J, Heimdal K, Møller P.

J Clin Oncol. 2005 Jul 20;23(21):4705-12.

PubMed [citation]
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000580477.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (5)


The c.2006-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 13 of the MSH2 gene. This mutation has been identified in multiple patients satisfying Amsterdam Criteria I (ACI) with tumors lacking MSH2 expression on IHC (Stormorken AT, J. Clin. Oncol. 2005 Jul; 23(21):4705-12; Sjursen W, J. Med. Genet. 2010 Sep; 47(9):579-85). This mutation was identified in an additional patient diagnosed at age 37 with CRC lacking MSH2 expression on IHC (Nagasaka T, Cancer Res. 2010 Apr; 70(8):3098-108), in a patient with an MSI-H tumor and/or a family history meeting AC criteria (Mangold E, Int. J. Cancer 2005 Sep; 116(5):692-702) and in a patient with colon cancer at 43 with loss of expression of MSH2 and MSH6 on IHC who also had bilateral renal cancer at ages 50 and 58 (Moussa SA et al. Int J Colorectal Dis, 2011 Apr;26:455-67). Of note, this mutation is also called IVS12-1G>C in published literature. 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.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Dec 4, 2021

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