NM_000251.3(MSH2):c.119del (p.Gly40fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 6, 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:: RCV002345384.3

Allele description [Variation Report for NM_000251.3(MSH2):c.119del (p.Gly40fs)]

NM_000251.3(MSH2):c.119del (p.Gly40fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.119del (p.Gly40fs)

HGVS:

NC_000002.12:g.47403310del
NG_007110.2:g.5187del
NM_000251.3:c.119delMANE SELECT
NM_001258281.1:c.-30-50del
NP_000242.1:p.Gly40fs
LRG_218:g.5187del
NC_000002.11:g.47630446del
NC_000002.11:g.47630449del
NM_000251.1:c.119del
NM_000251.1:c.119delG
NM_000251.2:c.119delG

Protein change:

G40fs

Links:

dbSNP: rs63750984

NCBI 1000 Genomes Browser:

rs63750984

Molecular consequence:

NM_000251.3:c.119del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258281.1:c.-30-50del - intron variant - [Sequence Ontology: SO:0001627]

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
SCV002647028	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 5, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11385712, 12626904, 24278394, 26300997 Citation Link,
SCV004356570	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 6, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11385712, 12626904, 21642682, 24278394, 26300997, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002647028

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 5, 2020)

germline

clinical testing

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

Citation Link,

SCV004356570

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 6, 2023)

germline

clinical testing

PubMed (6)
[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

Four novel MSH2 and MLH1 frameshift mutations and occurrence of a breast cancer phenocopy in hereditary nonpolyposis colorectal cancer.

Caluseriu O, Cordisco EL, Viel A, Majore S, Nascimbeni R, Pucciarelli S, Genuardi M.

Hum Mutat. 2001 Jun;17(6):521.

PubMed [citation]

PMID:: 11385712

Early-age-at-onset colorectal cancer and microsatellite instability as markers of hereditary nonpolyposis colorectal cancer.

Pucciarelli S, Agostini M, Viel A, Bertorelle R, Russo V, Toppan P, Lise M.

Dis Colon Rectum. 2003 Mar;46(3):305-12.

PubMed [citation]

PMID:: 12626904

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002647028.2

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

Description

The c.119delG pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 119, causing a translational frameshift with a predicted alternate stop codon (p.G40Afs*24). This mutation has been reported in multiple patients with hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome; including at least one patient whose tumor demonstrated microsatellite instability and had a family history meeting Amsterdam criteria (Caluseriu O et al. Hum Mutat, 2001 Jun;17:521; Pucciarelli S et al. Dis Colon Rectum, 2003 Mar;46:305-12; De Lellis L et al. PLoS One, 2013 Nov;8:e81194; Simbolo M et al. Hered Cancer Clin Pract, 2015 Aug;13:18). 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

From Color Diagnostics, LLC DBA Color Health, SCV004356570.1

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

Description

This variant deletes 1 nucleotide in exon 1 of the MSH2 gene, creating a frameshift and 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 and families affected with Lynch syndrome and Lynch syndrome-associated cancer (PMID: 11385712, 12626904, 21642682, 24278394, 26300997). 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

Last Updated: Sep 29, 2024

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