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NM_000251.3(MSH2):c.1386+1G>A AND Lynch syndrome

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Jun 21, 2019
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV000076137.6

Allele description

NM_000251.3(MSH2):c.1386+1G>A

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.1386+1G>A
HGVS:
  • NC_000002.12:g.47445658G>A
  • NG_007110.2:g.47535G>A
  • NM_000251.3:c.1386+1G>AMANE SELECT
  • NM_001258281.1:c.1188+1G>A
  • NM_001406631.1:c.1386+1G>A
  • NM_001406632.1:c.1386+1G>A
  • NM_001406633.1:c.1386+1G>A
  • NM_001406634.1:c.1386+1G>A
  • NM_001406635.1:c.1386+1G>A
  • NM_001406636.1:c.1353+1G>A
  • NM_001406637.1:c.1386+1G>A
  • NM_001406638.1:c.1386+1G>A
  • NM_001406639.1:c.1386+1G>A
  • NM_001406640.1:c.1386+1G>A
  • NM_001406641.1:c.1386+1G>A
  • NM_001406642.1:c.1386+1G>A
  • NM_001406643.1:c.1386+1G>A
  • NM_001406644.1:c.1386+1G>A
  • NM_001406645.1:c.1386+1G>A
  • NM_001406646.1:c.1386+1G>A
  • NM_001406647.1:c.1236+1G>A
  • NM_001406648.1:c.1386+1G>A
  • NM_001406649.1:c.1236+1G>A
  • NM_001406650.1:c.1236+1G>A
  • NM_001406651.1:c.1236+1G>A
  • NM_001406652.1:c.1236+1G>A
  • NM_001406653.1:c.1326+1G>A
  • NM_001406654.1:c.966+1G>A
  • NM_001406655.1:c.1386+1G>A
  • NM_001406656.1:c.489+1G>A
  • NM_001406657.1:c.1386+1G>A
  • NM_001406658.1:c.30+1G>A
  • NM_001406659.1:c.30+1G>A
  • NM_001406660.1:c.30+1G>A
  • NM_001406661.1:c.30+1G>A
  • NM_001406662.1:c.30+1G>A
  • NM_001406666.1:c.1386+1G>A
  • NM_001406669.1:c.30+1G>A
  • NM_001406672.1:c.1236+1G>A
  • NM_001406674.1:c.1386+1G>A
  • LRG_218t1:c.1386+1G>A
  • LRG_218:g.47535G>A
  • NC_000002.11:g.47672797G>A
  • NM_000251.1:c.1386+1G>A
  • NM_000251.2:c.1386+1G>A
Links:
dbSNP: rs267607957
NCBI 1000 Genomes Browser:
rs267607957
Molecular consequence:
  • NM_000251.3:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258281.1:c.1188+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406631.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406632.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406633.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406634.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406635.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406636.1:c.1353+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406637.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406638.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406639.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406640.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406641.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406642.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406643.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406644.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406645.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406646.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406647.1:c.1236+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406648.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406649.1:c.1236+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406650.1:c.1236+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406651.1:c.1236+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406652.1:c.1236+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406653.1:c.1326+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406654.1:c.966+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406655.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406656.1:c.489+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406657.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406658.1:c.30+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406659.1:c.30+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406660.1:c.30+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406661.1:c.30+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406662.1:c.30+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406666.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406669.1:c.30+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406672.1:c.1236+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406674.1:c.1386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
Observations:
1

Condition(s)

Name:
Lynch syndrome
Identifiers:
MONDO: MONDO:0005835; MedGen: C4552100

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000107152International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
reviewed by expert panel

(Guidelines v2.4)		Likely pathogenic
(Jun 21, 2019) 		germlinecuration

Citation Link,

SCV000592500Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Pathogenicunknownclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyes1not providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedcuration

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000107152.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Interrupts canonical donor splice site

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592500.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The c.1386+1G>A variant was identified in 3 of 3562 proband chromosomes (frequency: 0.001) from individuals or families with Lynch Syndrome (Auclair, 2006; Mangold, 2005). The variant was also identified in dbSNP (ID: rs267607957) “With pathogenic allele”, HGMD, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database” (as likely pathogenic), and the ClinVar database. The c.1386+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. Studies by Auclair and Betz have shown this variant to cause the loss of exon 8 and Mueller-Koch links this loss to a loss of expression of the MSH2 protein in colon tumours. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing in 4 of 5 programs. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Jun 9, 2024