NM_000251.3(MSH2):c.187del (p.Gly62_Val63insTer) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 30, 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:: RCV000491017.4

Allele description [Variation Report for NM_000251.3(MSH2):c.187del (p.Gly62_Val63insTer)]

NM_000251.3(MSH2):c.187del (p.Gly62_Val63insTer)

Gene:

MSH2:mutS homolog 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.187del (p.Gly62_Val63insTer)

HGVS:

NC_000002.12:g.47403378del
NG_007110.2:g.5255del
NM_000251.3:c.187delMANE SELECT
NM_001258281.1:c.-12del
NP_000242.1:p.Gly62_Val63insTer
NP_000242.1:p.Gly62_Val63insTer
LRG_218t1:c.187del
LRG_218:g.5255del
LRG_218p1:p.Gly62_Val63insTer
NC_000002.11:g.47630513del
NC_000002.11:g.47630517del
NM_000251.1:c.187del
NM_000251.1:c.187delG
NM_000251.2:c.187del
NM_000251.2:c.187delG

Links:

dbSNP: rs63750160

NCBI 1000 Genomes Browser:

rs63750160

Molecular consequence:

NM_001258281.1:c.-12del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000251.3:c.187del - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000580445	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 30, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12949792, 16216036, 24344984, 26437257, 27601186, 28874130, 31615790 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000580445

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 30, 2021)

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

Stromal expression of invasion-promoting, matrix-degrading proteases MMP-1 and -9 and the Ets 1 transcription factor in HNPCC carcinomas and sporadic colorectal cancers.

Behrens P, Mathiak M, Mangold E, Kirdorf S, Wellmann A, Fogt F, Rothe M, Florin A, Wernert N.

Int J Cancer. 2003 Nov 1;107(2):183-8.

PubMed [citation]

PMID:: 12949792

Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining.

Mangold E, Pagenstecher C, Friedl W, Fischer HP, Merkelbach-Bruse S, Ohlendorf M, Friedrichs N, Aretz S, Buettner R, Propping P, Mathiak M.

J Pathol. 2005 Dec;207(4):385-95.

PubMed [citation]

PMID:: 16216036

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000580445.6

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

Description

The c.187delG pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 187, causing a translational frameshift with a predicted alternate stop codon (p.V63*). This mutation has been reported in multiple HNPCC/Lynch syndrome patients; several whose tumors demonstrated loss of MSH2 staining by immunohistochemistry (IHC) (Behrens P et al. Int. J. Cancer, 2003 Nov;107:183-8; Mangold E et al. J Pathol, 2005 Dec;207:385-95; Dominguez-Valentin M et al. Hered Cancer Clin Pract, 2013 Dec;11:18; Carneiro da Silva F et al. PLoS One, 2015 Oct;10:e0139753; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199). This mutation was also identified in an individual diagnosed with breast cancer at age 55, whose breast tumor showed microsatellite instability and absent MSH2 and MSH6 staining on IHC (Lotsari JE et al. Breast Cancer Res. 2012 Jun 12;14(3):R90). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted 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 9, 2024

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