NM_000251.3(MSH2):c.2335dup (p.Met779fs) AND Lynch syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 5, 2013
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000076459.5

Allele description [Variation Report for NM_000251.3(MSH2):c.2335dup (p.Met779fs)]

NM_000251.3(MSH2):c.2335dup (p.Met779fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.2335dup (p.Met779fs)

HGVS:

NC_000002.12:g.47478396dup
NG_007110.2:g.80273dup
NM_000251.3:c.2335dupMANE SELECT
NM_001258281.1:c.2137dup
NP_000242.1:p.Met779fs
NP_000242.1:p.Met779fs
NP_001245210.1:p.Met713fs
LRG_218t1:c.2335dup
LRG_218:g.80273dup
LRG_218p1:p.Met779fs
NC_000002.11:g.47705534_47705535insA
NC_000002.11:g.47705535dup
NM_000251.1:c.2335dup
NM_000251.1:c.2335dupA
NM_000251.2:c.2335dup
NM_000251.2:c.2335dupA

Protein change:

M713fs

Links:

dbSNP: rs63750149

NCBI 1000 Genomes Browser:

rs63750149

Molecular consequence:

NM_000251.3:c.2335dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258281.1:c.2137dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Gm36774 predicted gene, 36774 [Mus musculus]
Gm36774 predicted gene, 36774 [Mus musculus]
Gene ID:102640791

Gene
Gm36774 AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000107488	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	Pathogenic (Sep 5, 2013)	germline	research	Citation Link,
SCV000917710	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 26, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000107488

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v1.9)

Pathogenic
(Sep 5, 2013)

germline

research

Citation Link,

SCV000917710

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 26, 2018)

germline

clinical testing

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

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, research

Citations

PubMed

Reduction in hMSH2 mRNA levels by premature translation termination: implications for mutation screening in hereditary nonpolyposis colorectal cancer.

Lin X, Choi JH, Lynch P, Xi L, Wu E, Frazier ML.

Dig Dis Sci. 1999 Mar;44(3):553-9.

PubMed [citation]

PMID:: 10080150

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000107488.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

Description

Coding sequence variation introducing premature termination codon

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917710.1

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

Description

Variant summary: MSH2 c.2335dupA (p.Met779AsnfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic/pathogenic by our laboratory (eg. c.2460_2462delinsA (p.Val821fsX2), c.2466T>A (p.Cys822X), and c.2633_2634delAG (p.Glu878fsX3)). The variant was absent in 246228 control chromosomes (gnomAD). The variant, c.2335dupA, has been reported in the literature in an individual affected with Lynch Syndrome (Lin_1999). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was 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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