NM_000251.3(MSH2):c.746del (p.Lys249fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 24, 2020
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:: RCV001380410.7

Allele description [Variation Report for NM_000251.3(MSH2):c.746del (p.Lys249fs)]

NM_000251.3(MSH2):c.746del (p.Lys249fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.746del (p.Lys249fs)

HGVS:

NC_000002.12:g.47412514del
NG_007110.2:g.14391del
NM_000251.3:c.746delMANE SELECT
NM_001258281.1:c.548del
NP_000242.1:p.Lys249fs
NP_001245210.1:p.Lys183fs
LRG_218:g.14391del
NC_000002.11:g.47639649del
NC_000002.11:g.47639653del
NM_000251.1:c.746del
NM_000251.1:c.746delA
p.K249RFS*5

Protein change:

K183fs

Links:

dbSNP: rs63749832

NCBI 1000 Genomes Browser:

rs63749832

Molecular consequence:

NM_000251.3:c.746del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258281.1:c.548del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001578475	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 24, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15849733, 24362816, 15571801, 21642682, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001578475

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 24, 2020)

germline

clinical testing

PubMed (5)
[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

Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer.

Mangold E, Pagenstecher C, Friedl W, Mathiak M, Buettner R, Engel C, Loeffler M, Holinski-Feder E, Müller-Koch Y, Keller G, Schackert HK, Krüger S, Goecke T, Moeslein G, Kloor M, Gebert J, Kunstmann E, Schulmann K, Rüschoff J, Propping P.

Int J Cancer. 2005 Sep 20;116(5):692-702.

PubMed [citation]

PMID:: 15849733

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capellá G, den Dunnen JT, du Sart D, Fabre A, Farrell MP, Farrington SM, Frayling IM, Frebourg T, Goldgar DE, Heinen CD, Holinski-Feder E, Kohonen-Corish M, Robinson KL, Leung SY, et al.

Nat Genet. 2014 Feb;46(2):107-115. doi: 10.1038/ng.2854. Epub 2013 Dec 22.

PubMed [citation]

PMID:: 24362816
PMCID:: PMC4294709

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001578475.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant has been observed in individual(s) with Lynch syndrome (PMID: 15571801, 21642682). ClinVar contains an entry for this variant (Variation ID: 91195). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys249Argfs*5) in the MSH2 gene. It is expected to result in an absent or disrupted protein product.

#	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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