NM_000251.3(MSH2):c.792+1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 1, 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:: RCV001026957.6

Allele description [Variation Report for NM_000251.3(MSH2):c.792+1G>A]

NM_000251.3(MSH2):c.792+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.792+1G>A

HGVS:

NC_000002.12:g.47412561G>A
NG_007110.2:g.14438G>A
NM_000251.3:c.792+1G>AMANE SELECT
NM_001258281.1:c.594+1G>A
NM_001406631.1:c.792+1G>A
NM_001406632.1:c.792+1G>A
NM_001406633.1:c.792+1G>A
NM_001406634.1:c.792+1G>A
NM_001406635.1:c.792+1G>A
NM_001406636.1:c.792+1G>A
NM_001406637.1:c.792+1G>A
NM_001406638.1:c.792+1G>A
NM_001406639.1:c.792+1G>A
NM_001406640.1:c.792+1G>A
NM_001406641.1:c.792+1G>A
NM_001406642.1:c.792+1G>A
NM_001406643.1:c.792+1G>A
NM_001406644.1:c.792+1G>A
NM_001406645.1:c.792+1G>A
NM_001406646.1:c.792+1G>A
NM_001406647.1:c.792+1G>A
NM_001406648.1:c.792+1G>A
NM_001406649.1:c.792+1G>A
NM_001406650.1:c.792+1G>A
NM_001406651.1:c.792+1G>A
NM_001406652.1:c.792+1G>A
NM_001406653.1:c.732+1G>A
NM_001406654.1:c.372+1G>A
NM_001406655.1:c.792+1G>A
NM_001406656.1:c.-204+1G>A
NM_001406657.1:c.792+1G>A
NM_001406658.1:c.-527+1G>A
NM_001406659.1:c.-677+1G>A
NM_001406660.1:c.-874+1G>A
NM_001406661.1:c.-829+1G>A
NM_001406662.1:c.-746+1G>A
NM_001406666.1:c.792+1G>A
NM_001406669.1:c.-677+1G>A
NM_001406672.1:c.792+1G>A
NM_001406674.1:c.792+1G>A
LRG_218t1:c.792+1G>A
LRG_218:g.14438G>A
NC_000002.11:g.47639700G>A
NM_000251.1:c.792+1G>A
NM_000251.2:c.792+1G>A

Links:

dbSNP: rs267607934

NCBI 1000 Genomes Browser:

rs267607934

Molecular consequence:

NM_000251.3:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001258281.1:c.594+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406631.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406632.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406633.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406634.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406635.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406636.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406637.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406638.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406639.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406640.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406641.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406642.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406643.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406644.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406645.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406646.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406647.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406648.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406649.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406650.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406651.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406652.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406653.1:c.732+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406654.1:c.372+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406655.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406656.1:c.-204+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406657.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406658.1:c.-527+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406659.1:c.-677+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406660.1:c.-874+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406661.1:c.-829+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406662.1:c.-746+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406666.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406669.1:c.-677+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406672.1:c.792+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406674.1:c.792+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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Chain E, Stathmin-4
Chain E, Stathmin-4
gi|257097274|pdb|3HKD|E

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001189437	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11524701, 15713769, 25117503 Citation Link,
SCV001354533	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 24, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001189437

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 1, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001354533

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 24, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas.

Cunningham JM, Kim CY, Christensen ER, Tester DJ, Parc Y, Burgart LJ, Halling KC, McDonnell SK, Schaid DJ, Walsh Vockley C, Kubly V, Nelson H, Michels VV, Thibodeau SN.

Am J Hum Genet. 2001 Oct;69(4):780-90. Epub 2001 Aug 24. Erratum in: Am J Hum Genet 2001 Nov;69(5):1160.

PubMed [citation]

PMID:: 11524701
PMCID:: PMC1226064

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Casey G, Lindor NM, Papadopoulos N, Thibodeau SN, Moskow J, Steelman S, Buzin CH, Sommer SS, Collins CE, Butz M, Aronson M, Gallinger S, Barker MA, Young JP, Jass JR, Hopper JL, Diep A, Bapat B, Salem M, Seminara D, Haile R; Colon Cancer Family Registry..

JAMA. 2005 Feb 16;293(7):799-809.

PubMed [citation]

PMID:: 15713769
PMCID:: PMC2933041

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV001189437.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The c.792+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the MSH2 gene. This variant has been identified in individuals meeting Amsterdam criteria with microsatellite unstable tumors also demonstrating loss of MSH2 and MSH6 protein expression by immunohistochemistry analysis (Cunningham JM et al. Am. J. Hum. Genet. 2001 Oct;69:780-90; Casey G et al. JAMA, 2005 Feb;293:799-809; Rosty C et al. Fam. Cancer 2014 Dec;13:573-82; Ambry internal data). The colon tumor of one of these patients was also found to have a somatic MSH2 mutation ("1165C>T, R389 stop") (Cunningham JM et al. Am. J. Hum. Genet. 2001 Oct;69:780-90). Additionally, conversion analysis confirmed that the c.792+1G>A variant results in coding exon 4 skipping (Casey G et al. JAMA 2005 Feb;293:799-809). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, 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

From Color Diagnostics, LLC DBA Color Health, SCV001354533.2

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

Description

This variant (also known as IVS4+1G>A) causes a G>A nucleotide substitution at the +1 position of intron 4 of the MSH2 gene. Functional RNA studies have shown that this variant causes exon 4 skipping resulting in loss of DNA binding domain (PMID: 15713769). This variant has been reported in individuals affected with colorectal cancer and Lynch syndrome (PMID: 11524701, 15713769, 23752102, 25117503). 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. 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

Last Updated: Sep 29, 2024

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