NM_000251.3(MSH2):c.1760-1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 8, 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:: RCV000491462.7

Allele description [Variation Report for NM_000251.3(MSH2):c.1760-1G>A]

NM_000251.3(MSH2):c.1760-1G>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.1760-1G>A

HGVS:

NC_000002.12:g.47475024G>A
NG_007110.2:g.76901G>A
NM_000251.3:c.1760-1G>AMANE SELECT
NM_001258281.1:c.1562-1G>A
NM_001406631.1:c.1760-1G>A
NM_001406632.1:c.1760-1G>A
NM_001406633.1:c.1760-1G>A
NM_001406634.1:c.1760-1G>A
NM_001406635.1:c.1760-1G>A
NM_001406636.1:c.1727-1G>A
NM_001406637.1:c.1760-1G>A
NM_001406638.1:c.1799-1G>A
NM_001406639.1:c.1760-1G>A
NM_001406640.1:c.1760-1G>A
NM_001406641.1:c.1760-1G>A
NM_001406642.1:c.1760-1G>A
NM_001406643.1:c.1760-1G>A
NM_001406644.1:c.1760-1G>A
NM_001406645.1:c.1760-1G>A
NM_001406646.1:c.1760-1G>A
NM_001406647.1:c.1610-1G>A
NM_001406648.1:c.1760-1G>A
NM_001406649.1:c.1610-1G>A
NM_001406650.1:c.1610-1G>A
NM_001406651.1:c.1610-1G>A
NM_001406652.1:c.1610-1G>A
NM_001406653.1:c.1700-1G>A
NM_001406654.1:c.1340-1G>A
NM_001406655.1:c.1760-1G>A
NM_001406656.1:c.863-1G>A
NM_001406657.1:c.1662-1G>A
NM_001406658.1:c.404-1G>A
NM_001406659.1:c.404-1G>A
NM_001406660.1:c.404-1G>A
NM_001406661.1:c.404-1G>A
NM_001406662.1:c.404-1G>A
NM_001406669.1:c.404-1G>A
NM_001406674.1:c.1760-1G>A
LRG_218t1:c.1760-1G>A
LRG_218:g.76901G>A
NC_000002.11:g.47702163G>A
NM_000251.1:c.1760-1G>A
NM_000251.2:c.1760-1G>A

Links:

dbSNP: rs587779110

NCBI 1000 Genomes Browser:

rs587779110

Molecular consequence:

NM_000251.3:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001258281.1:c.1562-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406631.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406632.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406633.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406634.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406635.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406636.1:c.1727-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406637.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406638.1:c.1799-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406639.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406640.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406641.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406642.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406643.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406644.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406645.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406646.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406647.1:c.1610-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406648.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406649.1:c.1610-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406650.1:c.1610-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406651.1:c.1610-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406652.1:c.1610-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406653.1:c.1700-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406654.1:c.1340-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406655.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406656.1:c.863-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406657.1:c.1662-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406658.1:c.404-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406659.1:c.404-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406660.1:c.404-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406661.1:c.404-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406662.1:c.404-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406669.1:c.404-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406674.1:c.1760-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000580446	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 2, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20459533, 22166501 Citation Link,
SCV000908316	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 8, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20459533, 22166501, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000580446

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 2, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000908316

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 8, 2022)

germline

clinical testing

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

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

Semiquantitative assessment of immunohistochemistry for mismatch repair proteins in Lynch syndrome.

Barrow E, Jagger E, Brierley J, Wallace A, Evans G, Hill J, McMahon R.

Histopathology. 2010 Feb;56(3):331-44. doi: 10.1111/j.1365-2559.2010.03485.x.

PubMed [citation]

PMID:: 20459533

Microsatellite instability in saliva from patients with hereditary non-polyposis colon cancer and siblings carrying germline mismatch repair gene mutations.

Hu P, Lee CW, Xu JP, Simien C, Fan CL, Tam M, Ramagli L, Brown BW, Lynch P, Frazier ML, Siciliano MJ, Coolbaugh-Murphy M.

Ann Clin Lab Sci. 2011 Fall;41(4):321-30.

PubMed [citation]

PMID:: 22166501

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000580446.6

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

Description

The c.1760-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide before coding exon 12 of the MSH2 gene. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability and/or loss of MSH2/MSH6 expression by immunohistochemistry (Ambry internal data). This variant has also been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH2/MSH6 expression by immunohistochemistry (Barrow E et al. Histopathology, 2010 Feb;56:331-44; Ambry internal data). In addition, this variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome (Hu P et al. Ann. Clin. Lab. Sci., 2011;41:321-30; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified 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, SCV000908316.2

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

Description

This variant causes a G to A nucleotide substitution at the -1 position of intron 11 of the MSH2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. . This variant has been reported in individuals affected with Lynch syndrome (PMID: 20459533, 22166501). 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 Likely 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: Oct 20, 2024

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