NM_000251.3(MSH2):c.862C>T (p.Gln288Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 3, 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:: RCV001183048.6

Allele description [Variation Report for NM_000251.3(MSH2):c.862C>T (p.Gln288Ter)]

NM_000251.3(MSH2):c.862C>T (p.Gln288Ter)

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.862C>T (p.Gln288Ter)

HGVS:

NC_000002.12:g.47414338C>T
NG_007110.2:g.16215C>T
NM_000251.3:c.862C>TMANE SELECT
NM_001258281.1:c.664C>T
NP_000242.1:p.Gln288Ter
NP_000242.1:p.Gln288Ter
NP_001245210.1:p.Gln222Ter
LRG_218t1:c.862C>T
LRG_218:g.16215C>T
LRG_218p1:p.Gln288Ter
NC_000002.11:g.47641477C>T
NM_000251.1:c.862C>T
NM_000251.2:c.862C>T

Protein change:

Q222*

Links:

dbSNP: rs63750097

NCBI 1000 Genomes Browser:

rs63750097

Molecular consequence:

NM_000251.3:c.862C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258281.1:c.664C>T - 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
SCV001348703	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7726159, 12547705, 15235030, 15849733, 24344984, 25741868
SCV002682471	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 27, 2019)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11151427, 12547705, 15235030, 15849733, 28874130, 9311737, 9634524 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001348703

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 3, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002682471

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 27, 2019)

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

Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient-gel electrophoresis.

Wijnen J, Vasen H, Khan PM, Menko FH, van der Klift H, van Leeuwen C, van den Broek M, van Leeuwen-Cornelisse I, Nagengast F, Meijers-Heijboer A, et al.

Am J Hum Genet. 1995 May;56(5):1060-6.

PubMed [citation]

PMID:: 7726159
PMCID:: PMC1801472

Mutation spectrum in South American Lynch syndrome families.

Dominguez-Valentin M, Nilbert M, Wernhoff P, López-Köstner F, Vaccaro C, Sarroca C, Palmero EI, Giraldo A, Ashton-Prolla P, Alvarez K, Ferro A, Neffa F, Caris J, Carraro DM, Rossi BM.

Hered Cancer Clin Pract. 2013 Dec 18;11(1):18. doi: 10.1186/1897-4287-11-18.

PubMed [citation]

PMID:: 24344984
PMCID:: PMC3904200

See all PubMed Citations (10)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001348703.3

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

Description

This variant changes 1 nucleotide in exon 5 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 7726159, 12547705, 15235030, 15849733, 24344984). 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, SCV002682471.2

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

Description

The p.Q288* pathogenic mutation (also known as c.862C>T), located in coding exon 5 of the MSH2 gene, results from a C to T substitution at nucleotide position 862. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This mutation has been identified in multiple HNPCC/Lynch syndrome families of various ethnicities, including patients whose tumors were MSI-H and demonstrated loss of MSH2 protein expression by IHC (Wijnen J et al. Am. J. Hum. Genet. 1997 Aug;61:329-35; Pistorius SR et al. Int. J Colorectal Dis, 2000 Nov;15:255-63; Hendriks Y et al. Am. J. Pathol. 2003 Feb;162:469-77; Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Rossi BM et al. BMC Cancer 2017 Sep;17:623). This mutation has also been reported in an individual with Muir-Torre phenotype who had colon cancer and multiple sebaceous skin tumors, one of which was shown to be MSI-H and demonstrated loss of MSH2 staining by IHC analysis (Kruse R et al. Am. J. Hum. Genet. 1998 Jul;63(1):63-70; Mangold E et al. J. Med. Genet., 2004 Jul;41:567-72). Of note, this alteration is also designated as p.Gln288*, p.Gln288X, "C to T at 862 (Gln to Stop)," Q288X, and "862CAG>TAG," in published literature. 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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