VCV001999169.3 - ClinVar

NM_000251.3(MSH2):c.1906_2005+8del

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000251.3(MSH2):c.1906_2005+8del

Variation ID: 1999169 Accession: VCV001999169.3

Type and length

Deletion, 108 bp

Location

Cytogenetic: 2p21 2: 47475167-47475274 (GRCh38) [ NCBI UCSC ] 2: 47702306-47702413 (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	Feb 8, 2023	Feb 20, 2024	Aug 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000251.3:c.1906_2005+8del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001258281.1:c.1708_1807+8del		splice donor
NM_001406655.1:c.1906_2013del108	NP_001393584.1:p.Ala636_Lys671del	inframe indel
NM_001406657.1:c.116_223del108
NC_000002.12:g.47475171_47475278del
NC_000002.11:g.47702310_47702417del
NG_007110.2:g.77048_77155del
LRG_218:g.77048_77155del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

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

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.
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Jun 7, 2022	RCV002815211.3
Lynch syndrome 1	Likely pathogenic (1)	criteria provided, single submitter	Aug 4, 2023	RCV003455583.1

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.
Likely pathogenic (Aug 04, 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: SCV004186652.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Publications: PubMed (1) PubMed: 3658675 Comment: This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either … (more) This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 3658675]. (less)
Pathogenic (Jun 07, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary nonpolyposis colorectal neoplasms Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003203379.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (10) PubMed: 12454801‚ 17101317‚ 18951462‚ 19101824‚ 21419771‚ 22102614‚ 23990280‚ 16199547‚ 15849733‚ 24362816 Comment: This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Ala636Pro) have been determined to be pathogenic (PMID: 12454801, 17101317, 18951462, 19101824, … (more) This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Ala636Pro) have been determined to be pathogenic (PMID: 12454801, 17101317, 18951462, 19101824, 21419771, 22102614, 23990280). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 12 (c.1906_2005+8del) of the MSH2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). (less)

Comment:

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 3658675].

Comment:

This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Ala636Pro) have been determined to be pathogenic (PMID: 12454801, 17101317, 18951462, 19101824, 21419771, 22102614, 23990280). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 12 (c.1906_2005+8del) of the MSH2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816).

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
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	Nature genetics	2014	PMID: 24362816
Lynch Syndrome in high risk Ashkenazi Jews in Israel.	Goldberg Y	Familial cancer	2014	PMID: 23990280
A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants.	Drost M	Human mutation	2012	PMID: 22102614
High risk of colorectal and endometrial cancer in Ashkenazi families with the MSH2 A636P founder mutation.	Mukherjee B	Gastroenterology	2011	PMID: 21419771
Homozygosity of MSH2 c.1906G-->C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I.	Toledano H	Familial cancer	2009	PMID: 19101824
Mechanisms of pathogenicity in human MSH2 missense mutants.	Ollila S	Human mutation	2008	PMID: 18951462
Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein.	Ollila S	Gastroenterology	2006	PMID: 17101317
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer.	Mangold E	International journal of cancer	2005	PMID: 15849733
The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population.	Foulkes WD	American journal of human genetics	2002	PMID: 12454801
RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression.	Shapiro MB	Nucleic acids research	1987	PMID: 3658675
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Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000251.3(MSH2):c.1906_2005+8del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...