VCV000429039.3 - ClinVar

NC_000002.11:g.38121110_47669522inv

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.

(1)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000002.11:g.38121110_47669522inv

Variation ID: 429039 Accession: VCV000429039.3

Type and length

Inversion, 9,548,413 bp

Location

Cytogenetic: 2p22.2-21 2: 38121110-47669522 (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	May 16, 2022	May 16, 2022	Nov 24, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NC_000002.11:g.38121110_47669522inv

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	7408	7570
SIX3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	199	226
CALM2		No evidence available	No evidence available	GRCh38 GRCh37	182	208
DHX57	-	No evidence available	No evidence available	GRCh38 GRCh37	108	134
SOS1		No evidence available	No evidence available	GRCh38 GRCh37	1681	1784
TMEM178A	-	No evidence available	No evidence available	GRCh38 GRCh37	15	39
ABCG5		-	-	GRCh38 GRCh37	181	748
ABCG8		-	-	GRCh38 GRCh37	745	811
ARHGEF33	-	-	-	GRCh38 GRCh37	42	81
ATL2		-	-	GRCh38 GRCh37	33	63

There are 44 more genes affected by this variant. See the full set of genes in Variation Viewer (GRCh37) and ClinGen Dosage Sensitivity Map.

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	Nov 24, 2021	RCV002231155.10

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 (Nov 24, 2021)	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: SCV000581402.3 First in ClinVar: Jul 02, 2017 Last updated: May 16, 2022	Publications: PubMed (2) PubMed: 12203789‚ 24114314 Comment: This sequence change is a complex rearrangement leading to the inversion of exons 1-7 of the MSH2 gene (c.-125-9509096_1277-3165inv). The 5' boundary is located ~9.5 … (more) This sequence change is a complex rearrangement leading to the inversion of exons 1-7 of the MSH2 gene (c.-125-9509096_1277-3165inv). The 5' boundary is located ~9.5 Mb upstream of the 5'UTR region (c.-125-9509096), and the 3' boundary is located in intron 7 (c.1277-3165). It is expected to result in an absent or disrupted protein product. This inversion event has been observed in individuals with Lynch syndrome (PMID: 12203789, 24114314). It has also been observed to segregate with disease in related individuals. This variant is also known as the 10-Mb paracentric inversion and the Boland inversion. ClinVar contains an entry for this variant (Variation ID: 429039). Studies have shown that this inversion alters MSH2 gene expression (PMID: 12203789). For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This sequence change is a complex rearrangement leading to the inversion of exons 1-7 of the MSH2 gene (c.-125-9509096_1277-3165inv). The 5' boundary is located ~9.5 Mb upstream of the 5'UTR region (c.-125-9509096), and the 3' boundary is located in intron 7 (c.1277-3165). It is expected to result in an absent or disrupted protein product. This inversion event has been observed in individuals with Lynch syndrome (PMID: 12203789, 24114314). It has also been observed to segregate with disease in related individuals. This variant is also known as the 10-Mb paracentric inversion and the Boland inversion. ClinVar contains an entry for this variant (Variation ID: 429039). Studies have shown that this inversion alters MSH2 gene expression (PMID: 12203789). For these reasons, this variant has been classified as 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
Inversion of exons 1-7 of the MSH2 gene is a frequent cause of unexplained Lynch syndrome in one local population.	Rhees J	Familial cancer	2014	PMID: 24114314
A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred.	Wagner A	Genes, chromosomes & cancer	2002	PMID: 12203789

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NC_000002.11:g.38121110_47669522inv

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...