NM_000251.3(MSH2):c.942+2T>A AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: May 4, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000251.3(MSH2):c.942+2T>A]


MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000002.12:g.47414420T>A
  • NG_007110.2:g.16297T>A
  • NM_000251.2:c.942+2T>A
  • NM_000251.3:c.942+2T>AMANE SELECT
  • NM_001258281.1:c.744+2T>A
  • LRG_218t1:c.942+2T>A
  • LRG_218:g.16297T>A
  • NC_000002.11:g.47641559T>A
  • NM_000251.1:c.942+2T>A
dbSNP: rs587779195
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000251.2:c.942+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_000251.3:c.942+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258281.1:c.744+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]


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)
SCV000580467Ambry Geneticscriteria provided, single submitter
(May 4, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001357860Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Mar 23, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]


This variant causes a T to A nucleotide substitution at the +2 position of intron 5 of the MSH2 gene. This variant is found adjacent to a poly-adenosine sequence, where the precise number of adenosine is difficult to determine via conventional sequencing technologies. Therefore, this variant may be reported by external laboratories as a deletion encompassing the +2T and varying number of adenosine, e.g. c.942+2del (ClinVar variation ID 91250) and c.942+2_942+6del (ClinVar variation ID 237416). All such variants are predicted to have the same splicing impact. 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 disrupt the DNA binding domain of the MSH2 protein. This variant has been reported in an individual affected with Lynch syndrome–associated cancer and/or polyps (PMID: 25980754). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.


Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms.

De Lellis L, Aceto GM, Curia MC, Catalano T, Mammarella S, Veschi S, Fantini F, Battista P, Stigliano V, Messerini L, Mareni C, Sala P, Bertario L, Radice P, Cama A.

PLoS One. 2013;8(11):e81194. doi: 10.1371/journal.pone.0081194.

PubMed [citation]

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

Details of each submission

From Ambry Genetics, SCV000580467.4

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


The c.942+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 5 in the MSH2 gene. This mutation has been reported in multiple individuals with Lynch syndrome-associate cancers who met Amsterdam I or II criteria or Bethesda Guidelines and whose tumors were MSI-H and showed absence of MSH2 on immunohistochemistry (de Lellis L at al. PLoS ONE 2013;8(11):e81194; Castillejo MI et al. eJIFCC Volume 27 no 1; February 2016). 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

From Color Health, Inc, SCV001357860.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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