VCV002584290.4 - ClinVar

NM_000535.7(PMS2):c.1144+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_000535.7(PMS2):c.1144+2T>G

Variation ID: 2584290 Accession: VCV002584290.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p22.1 7: 5989798 (GRCh38) [ NCBI UCSC ] 7: 6029429 (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	Oct 21, 2023	Aug 11, 2024	Jun 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000535.7:c.1144+2T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_000535.5:c.1144+2T>G
NM_001322003.2:c.739+2T>G		splice donor
NM_001322004.2:c.739+2T>G		splice donor
NM_001322005.2:c.739+2T>G		splice donor
NM_001322006.2:c.988+2175T>G		intron variant
NM_001322007.2:c.826+2T>G		splice donor
NM_001322008.2:c.826+2T>G		splice donor
NM_001322009.2:c.739+2T>G		splice donor
NM_001322010.2:c.583+2175T>G		intron variant
NM_001322011.2:c.211+2T>G		splice donor
NM_001322012.2:c.211+2T>G		splice donor
NM_001322013.2:c.571+2T>G		splice donor
NM_001322014.2:c.1144+2T>G		splice donor
NM_001322015.2:c.835+2T>G		splice donor
NM_001406866.1:c.1330+2T>G		splice donor
NM_001406868.1:c.1168+2T>G		splice donor
NM_001406869.1:c.1036+2T>G		splice donor
NM_001406870.1:c.988+2175T>G		intron variant
NM_001406871.1:c.1144+2T>G		splice donor
NM_001406872.1:c.1144+2T>G		splice donor
NM_001406873.1:c.946+2T>G		splice donor
NM_001406874.1:c.976+2T>G		splice donor
NM_001406875.1:c.835+2T>G		splice donor
NM_001406876.1:c.826+2T>G		splice donor
NM_001406877.1:c.835+2T>G		splice donor
NM_001406878.1:c.835+2T>G		splice donor
NM_001406879.1:c.835+2T>G		splice donor
NM_001406880.1:c.835+2T>G		splice donor
NM_001406881.1:c.835+2T>G		splice donor
NM_001406882.1:c.835+2T>G		splice donor
NM_001406883.1:c.826+2T>G		splice donor
NM_001406884.1:c.820+2175T>G		intron variant
NM_001406885.1:c.808+2T>G		splice donor
NM_001406886.1:c.778+2T>G		splice donor
NM_001406887.1:c.739+2T>G		splice donor
NM_001406888.1:c.739+2T>G		splice donor
NM_001406889.1:c.739+2T>G		splice donor
NM_001406890.1:c.739+2T>G		splice donor
NM_001406891.1:c.739+2T>G		splice donor
NM_001406892.1:c.739+2T>G		splice donor
NM_001406893.1:c.739+2T>G		splice donor
NM_001406894.1:c.739+2T>G		splice donor
NM_001406895.1:c.739+2T>G		splice donor
NM_001406896.1:c.739+2T>G		splice donor
NM_001406897.1:c.739+2T>G		splice donor
NM_001406898.1:c.739+2T>G		splice donor
NM_001406899.1:c.739+2T>G		splice donor
NM_001406900.1:c.679+2175T>G		intron variant
NM_001406901.1:c.670+2175T>G		intron variant
NM_001406902.1:c.670+2175T>G		intron variant
NM_001406903.1:c.826+2T>G		splice donor
NM_001406904.1:c.631+2T>G		splice donor
NM_001406905.1:c.631+2T>G		splice donor
NM_001406906.1:c.583+2175T>G		intron variant
NM_001406907.1:c.583+2175T>G		intron variant
NM_001406908.1:c.739+2T>G		splice donor
NM_001406909.1:c.571+2T>G		splice donor
NM_001406910.1:c.739+2T>G		splice donor
NM_001406911.1:c.373+2T>G		splice donor
NM_001406912.1:c.804-6807T>G		intron variant
NC_000007.14:g.5989798A>C
NC_000007.13:g.6029429A>C
NG_008466.1:g.24309T>G
LRG_161:g.24309T>G
LRG_161t1:c.1144+2T>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000007.14:5989797: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

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	5241	5343

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.
Lynch syndrome 4	Likely pathogenic (1)	criteria provided, single submitter	Jun 14, 2023	RCV003335738.2
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	May 18, 2023	RCV003594652.2
Hereditary cancer-predisposing syndrome	Likely pathogenic (1)	criteria provided, single submitter	Jun 20, 2024	RCV004654200.1

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 (Jun 14, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Lynch syndrome 4 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004045040.2 First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023	Comment: This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either … (more) This variant is considered likely 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. (less)
Pathogenic (May 18, 2023)	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: SCV004294442.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 16472587‚ 18602922‚ 22577899‚ 23837913‚ 26318770‚ 30521064 Comment: Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame … (more) Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (Invitae). For these reasons, this variant has been classified as Pathogenic. Other variant(s) that result in the loss of exon 10 have been determined to be pathogenic (PMID: 16472587, 18602922, 22577899, 23837913, 26318770). This suggests that this variant may also be clinically significant and likely to be disease-causing. Disruption of this splice site has been observed in individual(s) with colorectal cancer (PMID: 30521064). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 10 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. (less)
Likely pathogenic (Jun 20, 2024)	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: SCV005148288.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Comment: The c.1144+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 10 in the PMS2 gene. This nucleotide position is … (more) The c.1144+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 10 in the PMS2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)

Comment:

This variant is considered likely 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.

Comment:

Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (Invitae). For these reasons, this variant has been classified as Pathogenic. Other variant(s) that result in the loss of exon 10 have been determined to be pathogenic (PMID: 16472587, 18602922, 22577899, 23837913, 26318770). This suggests that this variant may also be clinically significant and likely to be disease-causing. Disruption of this splice site has been observed in individual(s) with colorectal cancer (PMID: 30521064). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 10 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.

Comment:

The c.1144+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 10 in the PMS2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features.	Jiang W	International journal of cancer	2019	PMID: 30521064
Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.	Lavoine N	Journal of medical genetics	2015	PMID: 26318770
High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families.	Brea-Fernández AJ	Clinical genetics	2014	PMID: 23837913
Recurrent and founder mutations in the PMS2 gene.	Tomsic J	Clinical genetics	2013	PMID: 22577899
The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.	Senter L	Gastroenterology	2008	PMID: 18602922
Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome).	Hendriks YM	Gastroenterology	2006	PMID: 16472587

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000535.7(PMS2):c.1144+2T>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...