VCV000619696.5 - ClinVar

NM_000251.3(MSH2):c.792+2T>G

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.

(3)

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.792+2T>G

Variation ID: 619696 Accession: VCV000619696.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p21 2: 47412562 (GRCh38) [ NCBI UCSC ] 2: 47639701 (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 15, 2019	May 1, 2024	Jul 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000251.3:c.792+2T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001258281.1:c.594+2T>G		splice donor
NM_001406631.1:c.792+2T>G		splice donor
NM_001406632.1:c.792+2T>G		splice donor
NM_001406633.1:c.792+2T>G		splice donor
NM_001406634.1:c.792+2T>G		splice donor
NM_001406635.1:c.792+2T>G		splice donor
NM_001406636.1:c.792+2T>G		splice donor
NM_001406637.1:c.792+2T>G		splice donor
NM_001406638.1:c.792+2T>G		splice donor
NM_001406639.1:c.792+2T>G		splice donor
NM_001406640.1:c.792+2T>G		splice donor
NM_001406641.1:c.792+2T>G		splice donor
NM_001406642.1:c.792+2T>G		splice donor
NM_001406643.1:c.792+2T>G		splice donor
NM_001406644.1:c.792+2T>G		splice donor
NM_001406645.1:c.792+2T>G		splice donor
NM_001406646.1:c.792+2T>G		splice donor
NM_001406647.1:c.792+2T>G		splice donor
NM_001406648.1:c.792+2T>G		splice donor
NM_001406649.1:c.792+2T>G		splice donor
NM_001406650.1:c.792+2T>G		splice donor
NM_001406651.1:c.792+2T>G		splice donor
NM_001406652.1:c.792+2T>G		splice donor
NM_001406653.1:c.732+2T>G		splice donor
NM_001406654.1:c.372+2T>G		splice donor
NM_001406655.1:c.792+2T>G		splice donor
NM_001406656.1:c.-204+2T>G		splice donor
NM_001406657.1:c.792+2T>G		splice donor
NM_001406658.1:c.-527+2T>G		splice donor
NM_001406659.1:c.-677+2T>G		splice donor
NM_001406660.1:c.-874+2T>G		splice donor
NM_001406661.1:c.-829+2T>G		splice donor
NM_001406662.1:c.-746+2T>G		splice donor
NM_001406666.1:c.792+2T>G		splice donor
NM_001406669.1:c.-677+2T>G		splice donor
NM_001406672.1:c.792+2T>G		splice donor
NM_001406674.1:c.792+2T>G		splice donor
NC_000002.12:g.47412562T>G
NC_000002.11:g.47639701T>G
NG_007110.2:g.14439T>G
LRG_218:g.14439T>G
LRG_218t1:c.792+2T>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:47412561:T:G

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

dbSNP: rs587782408 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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	Oct 2, 2017	RCV000759123.2
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Sep 6, 2022	RCV002422644.2
Lynch syndrome 1	Pathogenic (1)	criteria provided, single submitter	Jul 28, 2023	RCV003453556.1

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 (Oct 02, 2017)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000888233.2 First in ClinVar: Mar 15, 2019 Last updated: Jan 01, 2022
Pathogenic (Jul 28, 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: SCV004188112.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Publications: PubMed (1) PubMed: 15713769 Comment: This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an … (more) This variant is considered 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: 15713769]. (less)
Pathogenic (Sep 06, 2022)	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: SCV002676961.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The c.792+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 4 in the MSH2 gene. Alterations that disrupt … (more) The c.792+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 4 in the MSH2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)

Comment:

This variant is considered 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: 15713769].

Comment:

The c.792+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 4 in the MSH2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, 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
Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.	Casey G	JAMA	2005	PMID: 15713769

Text-mined citations for rs587782408 ...

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.792+2T>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587782408 ...