NM_000251.3(MSH2):c.1386+1G>A AND Hereditary nonpolyposis colon cancer

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 12, 2020
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:: RCV001268971.1

Allele description [Variation Report for NM_000251.3(MSH2):c.1386+1G>A]

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]

Condition(s)

Name:: Hereditary nonpolyposis colon cancer (HNPCC)
Synonyms:: Hereditary nonpolyposis colorectal cancer; Familial nonpolyposis colon cancer; Hereditary Nonpolyposis Colorectal Cancer Syndrome
Identifiers:: MONDO: MONDO:0018630; MedGen: C1333990; OMIM: PS120435

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000696210	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 12, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16395668, 15849733, 15955785, 11179758, 19669161, 30521064, 29967336 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000696210

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Nov 12, 2020)

germline

clinical testing

PubMed (7)
[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

Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing.

Auclair J, Busine MP, Navarro C, Ruano E, Montmain G, Desseigne F, Saurin JC, Lasset C, Bonadona V, Giraud S, Puisieux A, Wang Q.

Hum Mutat. 2006 Feb;27(2):145-54.

PubMed [citation]

PMID:: 16395668

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 (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696210.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: MSH2 c.1386+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. Publications reported experimental evidence, demonstrating that the variant resulted in the skipping of exon 8 (Auclair_2006, Betz_2010). The variant was absent in 248984 control chromosomes (gnomAD). c.1386+1G>A has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Auclair_2006, Mangold_2005, Mueller-Koch_2005, Betz_2010, Baert-Desurmont_2018, Jiang_2019). These data indicate that the variant is likely to be associated with disease. Three other submitters, including an expert panel (InSiGHT), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (2x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.

#	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: Jun 23, 2024

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