NM_000251.3(MSH2):c.2292G>A (p.Trp764Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 14, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000584494.6

Allele description [Variation Report for NM_000251.3(MSH2):c.2292G>A (p.Trp764Ter)]

NM_000251.3(MSH2):c.2292G>A (p.Trp764Ter)

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.2292G>A (p.Trp764Ter)

HGVS:

NC_000002.12:g.47478353G>A
NG_007110.2:g.80230G>A
NM_000251.3:c.2292G>AMANE SELECT
NM_001258281.1:c.2094G>A
NP_000242.1:p.Trp764Ter
NP_000242.1:p.Trp764Ter
NP_001245210.1:p.Trp698Ter
LRG_218t1:c.2292G>A
LRG_218:g.80230G>A
LRG_218p1:p.Trp764Ter
NC_000002.11:g.47705492G>A
NM_000251.1:c.2292G>A
NM_000251.2:c.2292G>A

Protein change:

W698*

Links:

dbSNP: rs63751105

NCBI 1000 Genomes Browser:

rs63751105

Molecular consequence:

NM_000251.3:c.2292G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001258281.1:c.2094G>A - 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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000690060	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 14, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15945244, 16736289, 16810763, 25741868
SCV002734149	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 14, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15945244, 16736289, 16810763, 23537056 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000690060

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 14, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002734149

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 14, 2020)

germline

clinical testing

PubMed (4)
[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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

[The first molecular analysis of a Hungarian HNPCC family: a novel MSH2 germline mutation].

Czakó L, Tiszlavicz L, Takács R, Baradnay G, Lonovics J, Cserni G, Závodná K, Bartosova Z.

Orv Hetil. 2005 May 15;146(20):1009-16. Hungarian.

PubMed [citation]

PMID:: 15945244

See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000690060.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant changes 1 nucleotide in exon 14 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 15945244, 16736289, 16810763). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is 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

From Ambry Genetics, SCV002734149.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.W764* pathogenic mutation (also known as c.2292G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2292. This changes the amino acid from a tryptophan to a stop codon within coding exon 14. This mutation, designated as p.W764X, has been reported in patients from various ethnicities who meet Amsterdam criteria (Czakó L et al. Orv Hetil, 2005 May;146:1009-16; Spaepen M et al. Fam Cancer, 2006;5:179-89; Wang XL et al. World J Gastroenterol, 2006 Jul;12:4074-7). A similar alteration (c.2291G>A) resulting in the same premature stop codon (designated p.Trp764X) as been reported in an individual with the Muir-Torre variant of Lynch syndrome whose colorectal cancer and hepatocellular carcinoma both demonstrated high microsatellite instability and MSH2-/MSH6- by IHC (Casper M et al. Scand J Gastroenterol, 2013 Mar;48:344-51). 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: Sep 29, 2024

ClinVar

Relating variation to medicine