VCV002032519.4 - ClinVar

NC_000002.12:g.47403113G>A

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000002.12:g.47403113G>A

Variation ID: 2032519 Accession: VCV002032519.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p21 2: 47403113 (GRCh38) [ NCBI UCSC ] 2: 47630252 (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	Apr 20, 2024	Aug 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000251.2:c.-79G>A
NM_001258281.1:c.-93G>A		5 prime UTR
NC_000002.12:g.47403113G>A
NC_000002.11:g.47630252G>A
NG_007110.2:g.4990G>A
NG_095167.1:g.317G>A
LRG_218:g.4990G>A
LRG_218t1:c.-79G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:47403112:G: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

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	7482	7648

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	Uncertain significance (1)	criteria provided, single submitter	Sep 25, 2022	RCV002877052.10
Lynch syndrome	Uncertain significance (1)	criteria provided, single submitter	Aug 15, 2023	RCV004007652.2
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Aug 2, 2023	RCV003585309.1

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.
Uncertain significance (Aug 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV004359286.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 3313277‚ 12519945 Comment: This variant causes an G to A nucleotide substitution at the -79 position in the 5' untranslated region in the MSH2 gene. This variant is … (more) This variant causes an G to A nucleotide substitution at the -79 position in the 5' untranslated region in the MSH2 gene. This variant is located distal to the Kozak consensus sequence (PMID: 3313277) and the variant nucleotide is observed in multiple reference species at this position (PMID: 12519945), which suggest that this change may be functionally tolerated. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Sep 25, 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: SCV003237663.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Comment: 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 … (more) 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. 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 occurs in a non-coding region of the MSH2 gene. It does not change the encoded amino acid sequence of the MSH2 protein. (less)
Uncertain Significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004825295.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (2) PubMed: 3313277‚ 12519945 Comment: This variant causes an G to A nucleotide substitution at the -79 position in the 5' untranslated region in the MSH2 gene. This variant is … (more) This variant causes an G to A nucleotide substitution at the -79 position in the 5' untranslated region in the MSH2 gene. This variant is located distal to the Kozak consensus sequence (PMID: 3313277) and the variant nucleotide is observed in multiple reference species at this position (PMID: 12519945), which suggest that this change may be functionally tolerated. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 1 Zygosity: Single Heterozygote

Comment:

This variant causes an G to A nucleotide substitution at the -79 position in the 5' untranslated region in the MSH2 gene. This variant is located distal to the Kozak consensus sequence (PMID: 3313277) and the variant nucleotide is observed in multiple reference species at this position (PMID: 12519945), which suggest that this change may be functionally tolerated. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

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. 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 occurs in a non-coding region of the MSH2 gene. It does not change the encoded amino acid sequence of the MSH2 protein.

Comment:

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
The UCSC Genome Browser Database.	Karolchik D	Nucleic acids research	2003	PMID: 12519945
An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs.	Kozak M	Nucleic acids research	1987	PMID: 3313277

Text-mined citations for this variant ...

Record last updated Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NC_000002.12:g.47403113G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...