VCV001200813.11 - ClinVar

NM_000251.3(MSH2):c.942+3A>C

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.

(5)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(3); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000251.3(MSH2):c.942+3A>C

Variation ID: 1200813 Accession: VCV001200813.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p21 2: 47414421 (GRCh38) [ NCBI UCSC ] 2: 47641560 (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	Aug 19, 2021	May 1, 2024	Jan 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000251.3:c.942+3A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001258281.1:c.744+3A>C		intron variant
NC_000002.12:g.47414421A>C
NC_000002.11:g.47641560A>C
NG_007110.2:g.16298A>C
LRG_218:g.16298A>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:47414420:A:C

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: rs193922376 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	Mar 31, 2021	RCV001565948.3
Hereditary nonpolyposis colorectal neoplasms	Uncertain significance (1)	criteria provided, single submitter	Jan 22, 2024	RCV001859406.4
Hereditary cancer-predisposing syndrome	Likely pathogenic (1)	criteria provided, single submitter	Feb 15, 2022	RCV002449370.2
Lynch syndrome 1	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 25, 2023	RCV003451813.2

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 (Mar 31, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001789399.1 First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021	Comment: Not observed in large population cohorts (Lek 2016); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or … (more) Not observed in large population cohorts (Lek 2016); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge (less)
Uncertain significance (Jan 22, 2024)	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: SCV002125541.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (11) PubMed: 17576681‚ 9536098‚ 8062247‚ 10978353‚ 15222003‚ 16395668‚ 19419416‚ 20682701‚ 21681552‚ 22883484‚ 24310308 Comment: This sequence change falls in intron 5 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. … (more) This sequence change falls in intron 5 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1200813). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.942+3 nucleotide in the MSH2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8062247, 10978353, 15222003, 16395668, 19419416, 20682701, 21681552, 22883484, 24310308). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Likely pathogenic (Feb 15, 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: SCV002683303.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 10978353‚ 15713769‚ 16395668‚ 18270343‚ 19267393‚ 19459153 Comment: The c.942+3A>C intronic variant results from an A to C substitution 3 nucleotides after coding exon 5 in the MSH2 gene. This variant was identified … (more) The c.942+3A>C intronic variant results from an A to C substitution 3 nucleotides after coding exon 5 in the MSH2 gene. This variant was identified in an individual whose early onset, MSI-H colon tumor demonstrated absent MSH2 and MSH6 by immunohistochemistry (IHC) along with a somatic pathogenic mutation in MSH2 (Ambry internal data). While this exact alteration has not been reported in the literature, an alteration at the same nucleotide position (c.942+3A>T) has been reported in numerous individuals meeting clinical diagnostic criteria for Lynch syndrome and has been shown by multiple functional studies to cause exon 5 skipping (South CD et al. J. Natl. Cancer Inst. 2008 Feb;100(4):277-81; Desai DC et al. J. Med. Genet. 2000 Sep;37(9):646-52; Arnold S et al. Hum. Mutat. 2009 May;30(5):757-70; Auclair J et al. Hum. Mutat. 2006 Feb;27(2):145-54; Casey G et al. JAMA. 2005 Feb;293(7):799-809; Chong G et al. Hum. Mutat. 2009 Aug;30(8):E797-812). Furthermore, RNA studies have demonstrated a different alteration at this same position (c.942+3A>G) results in abnormal splicing as well (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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: SCV004188173.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Publications: PubMed (1) PubMed: 8062247 Comment: This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8062247].
Likely pathogenic (Sep 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004196234.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023

Comment:

This sequence change falls in intron 5 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1200813). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.942+3 nucleotide in the MSH2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8062247, 10978353, 15222003, 16395668, 19419416, 20682701, 21681552, 22883484, 24310308). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The c.942+3A>C intronic variant results from an A to C substitution 3 nucleotides after coding exon 5 in the MSH2 gene. This variant was identified in an individual whose early onset, MSI-H colon tumor demonstrated absent MSH2 and MSH6 by immunohistochemistry (IHC) along with a somatic pathogenic mutation in MSH2 (Ambry internal data). While this exact alteration has not been reported in the literature, an alteration at the same nucleotide position (c.942+3A>T) has been reported in numerous individuals meeting clinical diagnostic criteria for Lynch syndrome and has been shown by multiple functional studies to cause exon 5 skipping (South CD et al. J. Natl. Cancer Inst. 2008 Feb;100(4):277-81; Desai DC et al. J. Med. Genet. 2000 Sep;37(9):646-52; Arnold S et al. Hum. Mutat. 2009 May;30(5):757-70; Auclair J et al. Hum. Mutat. 2006 Feb;27(2):145-54; Casey G et al. JAMA. 2005 Feb;293(7):799-809; Chong G et al. Hum. Mutat. 2009 Aug;30(8):E797-812). Furthermore, RNA studies have demonstrated a different alteration at this same position (c.942+3A>G) results in abnormal splicing as well (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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
ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis).	Hegde M	Genetics in medicine : official journal of the American College of Medical Genetics	2014	PMID: 24310308
Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer.	Skeldon SC	European urology	2013	PMID: 22883484
Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals.	Valentin MD	Familial cancer	2011	PMID: 21681552
The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease.	Woods MO	Gut	2010	PMID: 20682701
High frequency of exon deletions and putative founder effects in French Canadian Lynch syndrome families.	Chong G	Human mutation	2009	PMID: 19459153
Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene.	Tang R	Clinical genetics	2009	PMID: 19419416
Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics.	Arnold S	Human mutation	2009	PMID: 19267393
The frequency of Muir-Torre syndrome among Lynch syndrome families.	South CD	Journal of the National Cancer Institute	2008	PMID: 18270343
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing.	Auclair J	Human mutation	2006	PMID: 16395668
Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.	Casey G	JAMA	2005	PMID: 15713769
Association of colonic and endometrial carcinomas in Portuguese families with hereditary nonpolyposis colorectal carcinoma significantly increases the probability of detecting a pathogenic mutation in mismatch repair genes, primarily the MSH2 gene.	Lage PA	Cancer	2004	PMID: 15222003
Recurrent germline mutation in MSH2 arises frequently de novo.	Desai DC	Journal of medical genetics	2000	PMID: 10978353
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098
hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds.	Liu B	Cancer research	1994	PMID: 8062247
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Text-mined citations for rs193922376 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000251.3(MSH2):c.942+3A>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs193922376 ...