NM_000251.3(MSH2):c.746del (p.Lys249fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 24, 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:: RCV000164791.6

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 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
SCV000215470	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 24, 2022)	germline	clinical testing	Citation Link,
SCV004011749	Cancer Genomics Lab, PINUM Cancer Hospital	no assertion criteria provided	Pathogenic (Jan 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000215470

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 24, 2022)

germline

clinical testing

Citation Link,

SCV004011749

Cancer Genomics Lab, PINUM Cancer Hospital

no assertion criteria provided

Pathogenic
(Jan 13, 2022)

germline

clinical testing

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

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
Pakistani	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Details of each submission

From Ambry Genetics, SCV000215470.7

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

Description

The c.746delA pathogenic mutation, located in coding exon 4 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 746, causing a translational frameshift with a predicted alternate stop codon (p.K249Rfs*5). To date, this mutation has been observed in five French HNPCC families, including in a proband diagnosed with colorectal cancer at age 30 and a family history meeting Amsterdam criteria (Bonadona V et al. JAMA. 2011 Jun 8;305(22):2304-10; Rey JM et al. Cancer Genet Cytogenet. 2004 Dec;155(2):149-51). 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 Cancer Genomics Lab, PINUM Cancer Hospital, SCV004011749.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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