NM_000251.3(MSH2):c.2680dup (p.Met894fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 13, 2023
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:: RCV000214664.10

Allele description [Variation Report for NM_000251.3(MSH2):c.2680dup (p.Met894fs)]

NM_000251.3(MSH2):c.2680dup (p.Met894fs)

Gene:

MSH2:mutS homolog 2 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.2680dup (p.Met894fs)

Other names:

p.Met894AsnfsX5

HGVS:

NC_000002.11:g.47709960_47709961insA
NC_000002.12:g.47482824dup
NG_007110.2:g.84701dup
NM_000251.3:c.2680dupMANE SELECT
NM_001258281.1:c.2482dup
NP_000242.1:p.Met894fs
NP_001245210.1:p.Met828fs
LRG_218:g.84701dup
NC_000002.11:g.47709960_47709961insA
NC_000002.11:g.47709963_47709964insA
NC_000002.11:g.47709963dup
NC_000002.12:g.47482824_47482825insA
NM_000251.1:c.2680dupA
NM_000251.2:c.2680dupA
NM_000251.3:c.2680dupAMANE SELECT

Protein change:

M828fs

Links:

dbSNP: rs876658211

NCBI 1000 Genomes Browser:

rs876658211

Molecular consequence:

NM_000251.3:c.2680dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258281.1:c.2482dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000273149	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000908332	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 3, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 273149, 15713769, 27601186, 30077346, 30322717, 35430768, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000273149

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 13, 2023)

germline

clinical testing

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

Citation Link,

SCV000908332

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 3, 2023)

germline

clinical testing

PubMed (7)
[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

A Canadian view of bilingualism in Carolina.

Kelton J.

N C Med J. 1978 Mar;39(3):163-4. No abstract available.

PubMed [citation]

PMID:: 273149

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 (7)

Details of each submission

From Ambry Genetics, SCV000273149.8

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

Description

The c.2680dupA pathogenic mutation, located in coding exon 16 of the MSH2 gene, results from a duplication of one nucleotide at position c.2680 resulting in a translational frameshift with a predicted alternate stop codon (p.M894Nfs*5). This alteration occurs at the 3' terminus of the MSH2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 41 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant has been detected in multiple individuals diagnosed with colorectal cancer that demonstrated either high microsatellite instability (MSI-H) or absent MSH2 and/or MSH6 staining by immunohistochemistry (IHC) (Ambry internal data; Casey G et al. JAMA 2005 Feb; 293(7):799-809). 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

From Color Diagnostics, LLC DBA Color Health, SCV000908332.2

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

Description

This variant inserts 1 nucleotide in exon 16 of the MSH2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial, ovarian, and colorectal cancer (PMID: 15713769, 30077346, 30322717, PMID: 35430768; ClinVar SCV000273149.7) and in families with suspected Lynch syndrome (PMID: 27601186). A couple of the individuals affected with colorectal cancer had tumors with either loss of MSH2 and MSH6 protein via immunohistochemistry and/or high microsatellite instability (PMID: 15713769; ClinVar SCV000273149.7). This variant has been identified in 3/251144 chromosomes 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: Sep 29, 2024

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