NM_000251.3(MSH2):c.1386+1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 13, 2021
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:: RCV000491969.4

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 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
SCV000580476	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 13, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15849733, 15955785, 16395668, 19669161, 27556954, 30521064 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000580476

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 13, 2021)

germline

clinical testing

PubMed (6)
[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

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

Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer.

Mueller-Koch Y, Vogelsang H, Kopp R, Lohse P, Keller G, Aust D, Muders M, Gross M, Daum J, Schiemann U, Grabowski M, Scholz M, Kerker B, Becker I, Henke G, Holinski-Feder E.

Gut. 2005 Dec;54(12):1733-40. Epub 2005 Jun 14.

PubMed [citation]

PMID:: 15955785
PMCID:: PMC1774771

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000580476.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The c.1386+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the MSH2 gene. This mutation has been previously identified in individuals with personal and/or family histories suggestive of Lynch syndrome (Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Mueller-Koch Y et al. Gut 2005 Dec;54:1733-40; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). This mutation has been identified as somatic in conjunction with a somatic pathogenic MSH2 variant in a Lynch syndrome-associated tumor that demonstrated loss of MSH2/MSH6 expression by immunohistochemistry (IHC; Watkins JC et al. Int. J. Gynecol. Pathol. 2017 Mar;36:115-127). This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MSH2 or MSH2/MSH6 expression by IHC (Ambry internal data). Additionally, functional analyses have demonstrated that this alteration leads to the skipping of coding exon 8 (Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54; Betz B et al. J. Cancer Res. Clin. Oncol. 2010 Jan;136:123-34; 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 donor site. 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: Jun 23, 2024

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