VCV000090940.4 - ClinVar

NM_000251.3(MSH2):c.2240_2241del (p.Ile747fs)

Germline

Top reviewed classifications are shown here.

Submission summary:

3 submissions

3 submitters

3 conditions

Reviewed by expert panel

Pathogenic

Sep 2013 by International …

for Lynch Syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000251.3(MSH2):c.2240_2241del (p.Ile747fs)

Variation ID: 90940 Accession: VCV000090940.4

Type and length

Deletion, 2 bp

Location

Cytogenetic: 2p21 2: 47478300-47478301 (GRCh38) [ NCBI UCSC ] 2: 47705439-47705440 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 24, 2015	May 1, 2024	Sep 5, 2013

HGVS

Nucleotide	Protein	Molecular consequence
NM_000251.3:c.2240_2241del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000242.1:p.Ile747fs	frameshift
NM_000251.1:c.2240_2241delTA
NM_001258281.1:c.2042_2043del	NP_001245210.1:p.Ile681fs	frameshift
NC_000002.12:g.47478301_47478302del
NC_000002.11:g.47705440_47705441del
NG_007110.2:g.80178_80179del
LRG_218:g.80178_80179del

... more HGVS ... less HGVS

Protein change

I681fs, I747fs

Other names

Canonical SPDI

NC_000002.12:47478299:ATA:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA020347 dbSNP: rs63751036 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MSH2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	7404	7566

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Lynch syndrome	Pathogenic (1)	reviewed by expert panel	Sep 5, 2013	RCV000076442.4
Lynch syndrome 1	Pathogenic (1)	criteria provided, single submitter	Aug 8, 2023	RCV003452900.1
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Mar 15, 2021	RCV004019110.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 05, 2013)	reviewed by expert panel (Guidelines v1.9) Method: research	Lynch Syndrome Affected status: unknown Allele origin: germline	International Society for Gastrointestinal Hereditary Tumours (InSiGHT) Accession: SCV000107470.3 First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 Comment: Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs	Comment: Coding sequence variation introducing premature termination codon
Pathogenic (Aug 08, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Lynch syndrome 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004187016.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Pathogenic (Mar 15, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005033552.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 11007253‚ 18566915‚ 20877318‚ 21778331‚ 23588873‚ 25648859 Comment: The c.2240_2241delTA variant, located in coding exon 14 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 2240 to 2241, … (more) The c.2240_2241delTA variant, located in coding exon 14 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 2240 to 2241, causing a translational frameshift with a predicted alternate stop codon (p.I747Rfs*2). This mutation has been reported in the family of a Danish patient who was diagnosed with an astrocytoma at age 42 as well as metachronous colorectal cancer (Therkildsen C et al. Eur J Neurol, 2015 Apr;22:717-24). This mutation was also detected in a Spanish colorectal cancer patient who was diagnosed at age 41 and whose tumor showed high microsatellite instability and loss of MSH2 and MSH6 immunohistochemical staining (Pérez-Cabornero L et al. Cancer Prev Res (Phila), 2011 Oct;4:1546-55). (Garre P et al. Nat Genet, 2010 Oct;42:817-8; author reply 818). (Caldés T et al. Am J Gastroenterol, 2000 Sep;95:2389-90). 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. (less)

Comment:

The c.2240_2241delTA variant, located in coding exon 14 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 2240 to 2241, causing a translational frameshift with a predicted alternate stop codon (p.I747Rfs*2). This mutation has been reported in the family of a Danish patient who was diagnosed with an astrocytoma at age 42 as well as metachronous colorectal cancer (Therkildsen C et al. Eur J Neurol, 2015 Apr;22:717-24). This mutation was also detected in a Spanish colorectal cancer patient who was diagnosed at age 41 and whose tumor showed high microsatellite instability and loss of MSH2 and MSH6 immunohistochemical staining (Pérez-Cabornero L et al. Cancer Prev Res (Phila), 2011 Oct;4:1546-55). (Garre P et al. Nat Genet, 2010 Oct;42:817-8; author reply 818). (Caldés T et al. Am J Gastroenterol, 2000 Sep;95:2389-90). 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Glioblastomas, astrocytomas and oligodendrogliomas linked to Lynch syndrome.	Therkildsen C	European journal of neurology	2015	PMID: 25648859
Genotype-phenotype correlation in MMR mutation-positive families with Lynch syndrome.	Pérez-Cabornero L	International journal of colorectal disease	2013	PMID: 23588873
Characterization of new founder Alu-mediated rearrangements in MSH2 gene associated with a Lynch syndrome phenotype.	Pérez-Cabornero L	Cancer prevention research (Philadelphia, Pa.)	2011	PMID: 21778331
Reassessing the TARBP2 mutation rate in hereditary nonpolyposis colorectal cancer.	Garre P	Nature genetics	2010	PMID: 20877318
Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population.	Nilbert M	Familial cancer	2009	PMID: 18566915
New mutation in the hMSH2 gene in a Spanish Muir-Torre syndrome.	Caldés T	The American journal of gastroenterology	2000	PMID: 11007253
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.2240_2241del	-	-	-	-

Text-mined citations for rs63751036 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000251.3(MSH2):c.2240_2241del (p.Ile747fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs63751036 ...