NM_000251.3(MSH2):c.1764T>G (p.Tyr588Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 3, 2022
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:: RCV002399462.2

Allele description [Variation Report for NM_000251.3(MSH2):c.1764T>G (p.Tyr588Ter)]

NM_000251.3(MSH2):c.1764T>G (p.Tyr588Ter)

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.1764T>G (p.Tyr588Ter)

HGVS:

NC_000002.12:g.47475029T>G
NG_007110.2:g.76906T>G
NM_000251.3:c.1764T>GMANE SELECT
NM_001258281.1:c.1566T>G
NP_000242.1:p.Tyr588Ter
NP_001245210.1:p.Tyr522Ter
LRG_218:g.76906T>G
NC_000002.11:g.47702168T>G
NM_000251.1:c.1764T>G

Protein change:

Y522*

Links:

dbSNP: rs63750844

NCBI 1000 Genomes Browser:

rs63750844

Molecular consequence:

NM_000251.3:c.1764T>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001258281.1:c.1566T>G - 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
SCV002711767	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 3, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12655562, 15849733 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002711767

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 3, 2022)

germline

clinical testing

PubMed (2)
[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

Identification of six novel MSH2 and MLH1 germline mutations in HNPCC.

Krüger S, Plaschke J, Jeske B, Görgens H, Pistorius SR, Bier A, Kreuz FR, Theissig F, Aust DE, Saeger HD, Schackert HK.

Hum Mutat. 2003 Apr;21(4):445-6.

PubMed [citation]

PMID:: 12655562

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

Details of each submission

From Ambry Genetics, SCV002711767.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Y588* pathogenic mutation (also known as c.1764T>G), located in coding exon 12 of the MSH2 gene, results from a T to G substitution at nucleotide position 1764. This changes the amino acid from a tyrosine to a stop codon within coding exon 12. This mutation was detected in a patient with ovarian cancer at age 41, urinary bladder cancer at age 53 and six synchronous colon cancers at age 55. One of the colon tumors demonstrated high microsatellite instability and loss of MSH2 protein by immunohistochemistry (Krüger S et al. Hum Mutat, 2003 Apr;21:445-6). In a study of 1721 German probands suspected of HNPCC, this mutation was detected in one family (Mangold E et al. Int J Cancer, 2005 Sep;116:692-702). 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: May 7, 2024

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