ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.2444C>T (p.Ser815Leu)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000535.7(PMS2):c.2444C>T (p.Ser815Leu)
Variation ID: 91343 Accession: VCV000091343.27
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7p22.1 7: 5977589 (GRCh38) [ NCBI UCSC ] 7: 6017220 (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 Mar 24, 2015 May 1, 2024 Oct 18, 2018 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000535.7:c.2444C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Ser815Leu missense NM_001322003.2:c.2039C>T NP_001308932.1:p.Ser680Leu missense NM_001322004.2:c.2039C>T NP_001308933.1:p.Ser680Leu missense NM_001322005.2:c.2039C>T NP_001308934.1:p.Ser680Leu missense NM_001322006.2:c.2288C>T NP_001308935.1:p.Ser763Leu missense NM_001322007.2:c.2126C>T NP_001308936.1:p.Ser709Leu missense NM_001322008.2:c.2126C>T NP_001308937.1:p.Ser709Leu missense NM_001322009.2:c.2072C>T NP_001308938.1:p.Ser691Leu missense NM_001322010.2:c.1883C>T NP_001308939.1:p.Ser628Leu missense NM_001322011.2:c.1511C>T NP_001308940.1:p.Ser504Leu missense NM_001322012.2:c.1511C>T NP_001308941.1:p.Ser504Leu missense NM_001322013.2:c.1871C>T NP_001308942.1:p.Ser624Leu missense NM_001322014.2:c.2477C>T NP_001308943.1:p.Ser826Leu missense NM_001322015.2:c.2135C>T NP_001308944.1:p.Ser712Leu missense NR_136154.1:n.2488C>T non-coding transcript variant NC_000007.14:g.5977589G>A NC_000007.13:g.6017220G>A NG_008466.1:g.36518C>T LRG_161:g.36518C>T LRG_161t1:c.2444C>T - Protein change
- S815L, S709L, S763L, S504L, S628L, S680L, S691L, S712L, S624L, S826L
- Other names
- -
- Canonical SPDI
- NC_000007.14:5977588:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe 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 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
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 | ||
---|---|---|---|---|---|---|
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 |
5155 | 5249 |
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. |
---|---|---|---|---|
Likely pathogenic (3) |
reviewed by expert panel
|
Oct 18, 2018 | RCV000076859.7 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000485694.6 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 13, 2023 | RCV000130249.8 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 24, 2022 | RCV001193971.3 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 21, 2023 | RCV000525929.9 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 20, 2023 | RCV003452993.2 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000764719.3 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Oct 18, 2018)
|
reviewed by expert panel
Method: curation
|
Lynch syndrome
Affected status: yes
Allele origin:
germline
|
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000108351.3
First in ClinVar: Dec 19, 2013 Last updated: Jun 02, 2019 |
Comment:
Abrogated MMR activity in 2 independent labs, 4 MSI-H/IHC loss tumors, MAF<0.01, 1 Ams family with 2 non-proband affected carriers.
|
|
Uncertain significance
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Mismatch repair cancer syndrome 1
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000895854.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(May 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363169.2
First in ClinVar: Jun 22, 2020 Last updated: Jul 17, 2022 |
Comment:
Variant summary: PMS2 c.2444C>T (p.Ser815Leu) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. … (more)
Variant summary: PMS2 c.2444C>T (p.Ser815Leu) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1e-05 in 199430 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with colorectal cancer and other Lynch Syndrome related tumors (Brea-Fernandez_2013 , Gonzalez-Acosta_2017, van der Klift_2016). In one family the variant co-segregated with the disease (Gonzalez-Acosta_2017). The variant has also reported in the homozygous state in an individual with constitutional mismatch repair deficiency (Suerink_2017). Experimental evidence suggest that this variant significantly reduce mismatch repair activity and protein expression in vitro (Gonzalez-Acosta_2017, van der Klift_2016). Taken together, these data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Likely pathogenic
(Nov 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000565423.7
First in ClinVar: Apr 29, 2017 Last updated: Dec 11, 2022 |
Comment:
Published functional studies demonstrate a damaging effect: deficient mismatch repair activity (van der Klift et al., 2016); Observed in patients with Lynch-related cancers and tumor … (more)
Published functional studies demonstrate a damaging effect: deficient mismatch repair activity (van der Klift et al., 2016); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene and has been shown to segregate with affected individuals in one family (van der Klift et al., 2010; Suerink et al., 2016; ten Broeke et al., 2015; Gonzalez-Acosta et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26110232, 23837913, 25512458, 22675565, 22290698, 20186688, 23709753, 27435373, 23435383, 30013564, 28365877, Lukas2018, 28503822, 21552516, 29922827, 35451539, 35532657) (less)
|
|
Likely pathogenic
(Feb 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556879.2
First in ClinVar: Aug 04, 2022 Last updated: Dec 17, 2022 |
|
|
Pathogenic
(Dec 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000625619.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 815 of the PMS2 protein (p.Ser815Leu). … (more)
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 815 of the PMS2 protein (p.Ser815Leu). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individuals with Lynch syndrome (PMID: 20186688, 23837913, 25512458, 26110232, 27435373, 28503822; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91343). An algorithm developed specifically for the PMS2 gene suggests that this missense change is likely to be deleterious (PMID: 22290698). Experimental studies have shown that this missense change affects PMS2 function (PMID: 27435373, 28365877). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(Nov 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185093.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.S815L variant (also known as c.2444C>T), located in coding exon 14 of the PMS2 gene, results from a C to T substitution at nucleotide … (more)
The p.S815L variant (also known as c.2444C>T), located in coding exon 14 of the PMS2 gene, results from a C to T substitution at nucleotide position 2444. The serine at codon 815 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in several individuals with Lynch associated cancers that demonstrated high microsatellite instability (MSI-H) and/or loss of PMS2 on immunohistochemistry (IHC) (van der Klift HM et al. Hum. Mutat. 2010 May;31:578-87; van der Klift HM et al. Hum. Mutat. 2016 Nov;37:1162-1179). It has also been reported in a homozygous state in a child with features of CMMRD and demonstrated severely impaired mismatch activity in an in vitro functional assay (van der Klift HM et al. Hum. Mutat. 2016 Nov;37:1162-1179; Suerink M et al. Clin. Genet. 2018 Jan;93:134-137). This alteration was also identified in three affected individuals of a family that met Amsterdam II criteria, and the colorectal tumor of the proband as well as the ovarian tumor of the mother showed MSI-H with loss of PMS2 on IHC (Brea-Fernández AJ et al. Clin. Genet. 2014 Jun;85:583-8; Gonzalez-Acosta M et al. Fam. Cancer 2017 Oct;16(4):501-507). Additional in vitro functional assays demonstrated decreased MLH1 and PMS2 protein expression as well as impaired MMR activity for the p.S815L variant (Gonzalez-Acosta M et al. Fam. Cancer 2017 Oct;16(4):501-507). Based on internal structural assessment, this alteration is expected to disrupt the interaction of PMS2 with MLH1 (Ambry internal data; Gueneau E et al. Nat. Struct. Mol. Biol. 2013 Apr;20:461-8). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
Likely pathogenic
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004024372.2
First in ClinVar: Aug 13, 2023 Last updated: Aug 18, 2023 |
|
|
Likely pathogenic
(Sep 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004187599.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function … (more)
This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 27435373]. (less)
|
|
Likely pathogenic
(Oct 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004205369.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Sep 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004358984.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces serine with leucine at codon 815 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces serine with leucine at codon 815 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional assays have reported that this variant protein have significantly reduced mismatch repair activity and protein expression compared to wild type (PMID: 27435373, 28365877). This variant has been reported in multiple individuals and families affected with Lynch syndrome-associated cancers (PMID: 20186688, 23837913, 25512458, 26110232, 27435373, 28365877; https://www.lovd.nl/), and has been observed to segregate with disease in one family (PMID: 28365877). This variant has also been observed in a homozygous carrier affected with constitutional mismatch repair deficiency (PMID: 28503822). This variant has been identified in 2/199430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
Likely Pathogenic
(Aug 06, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848114.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Ser815Leu variant in PMS2 has been reported in the heterozygous state in at least 3 individuals with PMS2-related cancers and segregated with disease in … (more)
The p.Ser815Leu variant in PMS2 has been reported in the heterozygous state in at least 3 individuals with PMS2-related cancers and segregated with disease in 2 affected members of one family (van der Klift 2010, Brea-Fernández 2014, ten Broeke 2015, van der Klift 2016, González-Acosta 2017). It has also been reported in the homozygous or compound heterozygous state in 2 individuals with features of congenital mismatch repair deficiency (CMMRD) and absence of PMS2 protein by IHC (Suerink 2016 and 2018, University of Washington personal communication). This variant has been identified in 0.008% (1/12702) of African chromosomes in gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies suggest that this variant leads to reduced PMS2 protein levels and deficiencies in mismatch repair (van der Klift 2016, González-Acosta 2017). Computational prediction tools and conservation analyses support that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Finally, this variant was classified as Likely Pathogenic on Oct. 18, 2018 by the ClinGen-approved InSiGHT expert panel (SCV000108351.3). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PM3, PS3_Moderate, PP3, PS4_Supporting. (less)
|
|
click to load more click to collapse |
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Repertoire Sequencing of B Cells Elucidates the Role of UNG and Mismatch Repair Proteins in Somatic Hypermutation in Humans. | IJspeert H | Frontiers in immunology | 2019 | PMID: 31507588 |
No Overt Clinical Immunodeficiency Despite Immune Biological Abnormalities in Patients With Constitutional Mismatch Repair Deficiency. | Tesch VK | Frontiers in immunology | 2018 | PMID: 30013564 |
Constitutional mismatch repair deficiency in a healthy child: On the spot diagnosis? | Suerink M | Clinical genetics | 2018 | PMID: 28503822 |
Elucidating the clinical significance of two PMS2 missense variants coexisting in a family fulfilling hereditary cancer criteria. | González-Acosta M | Familial cancer | 2017 | PMID: 28365877 |
Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome. | van der Klift HM | Human mutation | 2016 | PMID: 27435373 |
The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers. | Suerink M | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26110232 |
Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. | ten Broeke SW | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25512458 |
High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families. | Brea-Fernández AJ | Clinical genetics | 2014 | PMID: 23837913 |
Structure of the MutLα C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site. | Gueneau E | Nature structural & molecular biology | 2013 | PMID: 23435383 |
Classification of mismatch repair gene missense variants with PON-MMR. | Ali H | Human mutation | 2012 | PMID: 22290698 |
Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients. | van der Klift HM | Human mutation | 2010 | PMID: 20186688 |
http://www.insight-database.org/classifications/?gene=PMS2&variant=c.2444C%3ET | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs587779338 ...
HelpRecord last updated Jun 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.