NM_000251.3(MSH2):c.34dup (p.Glu12fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 14, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000221149.4

Allele description [Variation Report for NM_000251.3(MSH2):c.34dup (p.Glu12fs)]

NM_000251.3(MSH2):c.34dup (p.Glu12fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.34dup (p.Glu12fs)

HGVS:

NC_000002.12:g.47403225dup
NG_007110.2:g.5102dup
NM_000251.3:c.34dupMANE SELECT
NM_001258281.1:c.-31+50dup
NP_000242.1:p.Glu12fs
NP_000242.1:p.Glu12fs
LRG_218t1:c.34dup
LRG_218:g.5102dup
LRG_218p1:p.Glu12fs
NC_000002.11:g.47630362_47630363insG
NC_000002.11:g.47630364dup
NM_000251.1:c.34dup
NM_000251.1:c.34dupG
NM_000251.2:c.34dup
NM_000251.2:c.34dupG

Protein change:

E12fs

Links:

dbSNP: rs63750614

NCBI 1000 Genomes Browser:

rs63750614

Molecular consequence:

NM_000251.3:c.34dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258281.1:c.-31+50dup - 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
SCV000276142	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 14, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 14504054, 21550136 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000276142

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 14, 2022)

germline

clinical testing

PubMed (2)
[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

Microsatellite instability and mutation analysis among southern Italian patients with colorectal carcinoma: detection of different alterations accounting for MLH1 and MSH2 inactivation in familial cases.

Colombino M, Cossu A, Arba A, Manca A, Curci A, Avallone A, Comella G, Botti G, Scintu F, Amoruso M, D'Abbicco D, d'Agnessa MR, Spanu A, Tanda F, Palmieri G.

Ann Oncol. 2003 Oct;14(10):1530-6.

PubMed [citation]

PMID:: 14504054

Immunosuppression and sebaceous tumors: a confirmed diagnosis of Muir-Torre syndrome unmasked by immunosuppressive therapy.

Landis MN, Davis CL, Bellus GA, Wolverton SE.

J Am Acad Dermatol. 2011 Nov;65(5):1054-1058.e1. doi: 10.1016/j.jaad.2010.08.003. Epub 2011 May 6.

PubMed [citation]

PMID:: 21550136

Details of each submission

From Ambry Genetics, SCV000276142.8

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

Description

The c.34dupG pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a duplication of G at nucleotide position 34, causing a translational frameshift with a predicted alternate stop codon (p.E12Gfs*70). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with MSH2-related disease (Ambry internal data). In one study, this mutation was detected in 3/36 colorectal cancer families tested (Colombino M et al. Ann. Oncol. 2003 Oct;14:1530-6). This mutation has also been reported in a male with Muir-Torre syndrome; he had multiple (>30) sebaceous adenomas and sebaceous carcinomas and family history of colon cancer in his father, brother, paternal uncles, and cousin (Landis MN et al. J. Am. Acad. Dermatol. 2011 Nov;65:1054-1058.e1). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as "c.34_35insG" 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: Jun 9, 2024

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