VCV000648932.1 - ClinVar

NM_000535.5(PMS2):c.904-10_*10del

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

NM_000535.5(PMS2):c.904-10_*10del

Variation ID: 648932 Accession: VCV000648932.1

Type and length

Deletion, 18,679 bp

Location

Cytogenetic: 7p22.1 7: 5973389-5992067 (GRCh38) [ 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 14, 2019	Aug 14, 2019	Jan 3, 2019

HGVS

Nucleotide	Protein	Molecular consequence
NC_000007.14:g.5973389_5992067del
LRG_161t1:c.904-10_*10del

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.
PMS2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	5326	5429

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	Jan 3, 2019	RCV000803763.3

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 (Jan 03, 2019)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary nonpolyposis colon cancer Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000943649.1 First in ClinVar: Aug 14, 2019 Last updated: Aug 14, 2019	Publications: PubMed (8) PubMed: 20533529‚ 17258725‚ 24440087‚ 16338176‚ 21618646‚ 26318770‚ 23629955‚ 10037723 Comment: This variant is a gross deletion of the genomic region encompassing exons 9-15 of the PMS2 gene. The 5' boundary is likely confined to intron … (more) This variant is a gross deletion of the genomic region encompassing exons 9-15 of the PMS2 gene. The 5' boundary is likely confined to intron 8. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. Similar deletions of exons 9-15 have been observed in an individual affected with Lynch syndrome (PMID: 21618646), an individual affected with colorectal cancer (PMID: 17258725), and an individual affected with constitutional mismatch repair deficiency (PMID: 23629955).Â¬â€ ClinVar contains an entry for this variant (Variation ID: 455093). Sub-genic deletion of exons 14-15 disrupting the C-terminal portion of the MLH1 interaction domain required for PMS2-MLH1 dimerization (PMID: 10037723) and mismatch repair activity (PMID: 16338176, 20533529) has been determined to be pathogenic (PMID: 21618646, 24440087, 26318770,Â¬â€ Invitae).Â¬â€ Therefore, deletions that fully encompass that region are also expected to be pathogenic. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This variant is a gross deletion of the genomic region encompassing exons 9-15 of the PMS2 gene. The 5' boundary is likely confined to intron 8. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. Similar deletions of exons 9-15 have been observed in an individual affected with Lynch syndrome (PMID: 21618646), an individual affected with colorectal cancer (PMID: 17258725), and an individual affected with constitutional mismatch repair deficiency (PMID: 23629955).Â¬â€ ClinVar contains an entry for this variant (Variation ID: 455093). Sub-genic deletion of exons 14-15 disrupting the C-terminal portion of the MLH1 interaction domain required for PMS2-MLH1 dimerization (PMID: 10037723) and mismatch repair activity (PMID: 16338176, 20533529) has been determined to be pathogenic (PMID: 21618646, 24440087, 26318770,Â¬â€ Invitae).Â¬â€ Therefore, deletions that fully encompass that region are also expected to be pathogenic. 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
Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.	Lavoine N	Journal of medical genetics	2015	PMID: 26318770
Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium.	Bakry D	European journal of cancer (Oxford, England : 1990)	2014	PMID: 24440087
Multiple pilomatricomas with somatic CTNNB1 mutations in children with constitutive mismatch repair deficiency.	Chmara M	Genes, chromosomes & cancer	2013	PMID: 23629955
Avoidance of pseudogene interference in the detection of 3' deletions in PMS2.	Vaughn CP	Human mutation	2011	PMID: 21618646
Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair.	Kosinski J	Human mutation	2010	PMID: 20533529
Homozygous PMS2 deletion causes a severe colorectal cancer and multiple adenoma phenotype without extraintestinal cancer.	Will O	Gastroenterology	2007	PMID: 17258725
Truncation of the C-terminus of human MLH1 blocks intracellular stabilization of PMS2 and disrupts DNA mismatch repair.	Mohd AB	DNA repair	2006	PMID: 16338176
The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer.	Guerrette S	The Journal of biological chemistry	1999	PMID: 10037723

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000535.5(PMS2):c.904-10_*10del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...