VCV000215994.14 - ClinVar

NM_000535.7(PMS2):c.537+1G>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.

(6)

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.

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.537+1G>A

Variation ID: 215994 Accession: VCV000215994.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p22.1 7: 6002452 (GRCh38) [ NCBI UCSC ] 7: 6042083 (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	Jan 31, 2016	Nov 24, 2024	May 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000535.7:c.537+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_000535.6:c.537+1G>A
NM_001322003.2:c.132+1G>A		splice donor
NM_001322004.2:c.132+1G>A		splice donor
NM_001322005.2:c.132+1G>A		splice donor
NM_001322006.2:c.537+1G>A		splice donor
NM_001322007.2:c.219+1G>A		splice donor
NM_001322008.2:c.219+1G>A		splice donor
NM_001322009.2:c.132+1G>A		splice donor
NM_001322010.2:c.132+1G>A		splice donor
NM_001322011.2:c.-348+1G>A		splice donor
NM_001322012.2:c.-348+1G>A		splice donor
NM_001322013.2:c.132+1G>A		splice donor
NM_001322014.2:c.537+1G>A		splice donor
NM_001322015.2:c.228+1G>A		splice donor
NM_001406866.1:c.723+1G>A		splice donor
NM_001406868.1:c.561+1G>A		splice donor
NM_001406869.1:c.537+1G>A		splice donor
NM_001406870.1:c.537+1G>A		splice donor
NM_001406871.1:c.537+1G>A		splice donor
NM_001406872.1:c.537+1G>A		splice donor
NM_001406873.1:c.537+1G>A		splice donor
NM_001406874.1:c.537+1G>A		splice donor
NM_001406875.1:c.228+1G>A		splice donor
NM_001406876.1:c.219+1G>A		splice donor
NM_001406877.1:c.228+1G>A		splice donor
NM_001406878.1:c.228+1G>A		splice donor
NM_001406879.1:c.228+1G>A		splice donor
NM_001406880.1:c.228+1G>A		splice donor
NM_001406881.1:c.228+1G>A		splice donor
NM_001406882.1:c.228+1G>A		splice donor
NM_001406883.1:c.219+1G>A		splice donor
NM_001406884.1:c.537+1G>A		splice donor
NM_001406885.1:c.250+1520G>A		intron variant
NM_001406886.1:c.537+1G>A		splice donor
NM_001406887.1:c.132+1G>A		splice donor
NM_001406888.1:c.132+1G>A		splice donor
NM_001406889.1:c.132+1G>A		splice donor
NM_001406890.1:c.132+1G>A		splice donor
NM_001406891.1:c.132+1G>A		splice donor
NM_001406892.1:c.132+1G>A		splice donor
NM_001406893.1:c.132+1G>A		splice donor
NM_001406894.1:c.132+1G>A		splice donor
NM_001406895.1:c.132+1G>A		splice donor
NM_001406896.1:c.132+1G>A		splice donor
NM_001406897.1:c.132+1G>A		splice donor
NM_001406898.1:c.132+1G>A		splice donor
NM_001406899.1:c.132+1G>A		splice donor
NM_001406900.1:c.228+1G>A		splice donor
NM_001406901.1:c.219+1G>A		splice donor
NM_001406902.1:c.219+1G>A		splice donor
NM_001406903.1:c.219+1G>A		splice donor
NM_001406904.1:c.132+1G>A		splice donor
NM_001406905.1:c.132+1G>A		splice donor
NM_001406906.1:c.132+1G>A		splice donor
NM_001406907.1:c.132+1G>A		splice donor
NM_001406908.1:c.132+1G>A		splice donor
NM_001406909.1:c.132+1G>A		splice donor
NM_001406910.1:c.132+1G>A		splice donor
NM_001406911.1:c.132+1G>A		splice donor
NM_001406912.1:c.537+1G>A		splice donor
NC_000007.14:g.6002452C>T
NC_000007.13:g.6042083C>T
NG_008466.1:g.11655G>A
LRG_161:g.11655G>A
LRG_161t1:c.537+1G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000007.14:6002451:C:T

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA339064 dbSNP: rs863224450 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	5242	5344

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	Likely pathogenic (1)	criteria provided, single submitter	Jul 26, 2023	RCV001377722.7
Hereditary cancer-predisposing syndrome	Likely pathogenic (1)	criteria provided, single submitter	Feb 26, 2021	RCV002345713.2
Lynch syndrome 4 Mismatch repair cancer syndrome 4	Likely pathogenic (1)	criteria provided, single submitter	May 13, 2022	RCV002485315.1
Lynch syndrome 4	Likely pathogenic (1)	criteria provided, single submitter	Sep 19, 2023	RCV003454495.1
PMS2-related disorder	Likely pathogenic (1)	no assertion criteria provided	Jun 22, 2024	RCV004725052.1
not provided	Likely pathogenic (1)	criteria provided, single submitter	May 7, 2024	RCV004786533.1

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 (May 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 4 Mismatch repair cancer syndrome 4 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002800612.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely pathogenic (Sep 19, 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: SCV004187586.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 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)
Likely pathogenic (Jul 26, 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: SCV001575122.4 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 20587412‚ 31992580‚ 16199547‚ 21376568‚ 24362816 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 215994). Disruption of this splice site has been observed in individual(s) with colorectal cancer (PMID: 20587412, 31992580). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects a donor splice site in intron 5 of the PMS2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). (less)
Likely pathogenic (Feb 26, 2021)	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: SCV002645128.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 31992580 Comment: The c.537+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the PMS2 gene. This nucleotide position is … (more) The c.537+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the PMS2 gene. This nucleotide position is highly conserved in available vertebrate species. This variant is reported in an individual diagnosed with MSI-H colorectal cancer at age 55 (Wang Q et al. J Med Genet, 2020 07;57:487-499). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. (less)
Likely pathogenic (May 07, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005401433.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Comment: Observed in an individual with colorectal cancer (PMID: 31992580); Canonical splice site variant predicted to result in a null allele in a gene for which … (more) Observed in an individual with colorectal cancer (PMID: 31992580); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20587412, 29922827, 31992580) (less)
Likely pathogenic (Jun 22, 2024)	no assertion criteria provided Method: clinical testing	PMS2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005338912.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The PMS2 c.537+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in an individual with … (more) The PMS2 c.537+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in an individual with colorectal cancer (Wang et al. 2020. PubMed ID: 31992580). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant has been interpreted as likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/215994/). Variants that disrupt the consensus splice donor site in PMS2 are expected to be pathogenic. This variant is interpreted as likely 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:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 215994). Disruption of this splice site has been observed in individual(s) with colorectal cancer (PMID: 20587412, 31992580). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects a donor splice site in intron 5 of the PMS2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816).

Comment:

The c.537+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the PMS2 gene. This nucleotide position is highly conserved in available vertebrate species. This variant is reported in an individual diagnosed with MSI-H colorectal cancer at age 55 (Wang Q et al. J Med Genet, 2020 07;57:487-499). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

Comment:

Observed in an individual with colorectal cancer (PMID: 31992580); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20587412, 29922827, 31992580)

Comment:

The PMS2 c.537+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in an individual with colorectal cancer (Wang et al. 2020. PubMed ID: 31992580). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant has been interpreted as likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/215994/). Variants that disrupt the consensus splice donor site in PMS2 are expected to be pathogenic. This variant is interpreted as likely 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
Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome.	Wang Q	Journal of medical genetics	2020	PMID: 31992580
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.	Thompson BA	Nature genetics	2014	PMID: 24362816
Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines.	Herkert JC	European journal of cancer (Oxford, England : 1990)	2011	PMID: 21376568
Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers.	Sjursen W	Journal of medical genetics	2010	PMID: 20587412
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs863224450 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000535.7(PMS2):c.537+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs863224450 ...