ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.383C>T (p.Ser128Leu)
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.
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.
Uncertain significance(4); Benign(4); Likely benign(9)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.383C>T (p.Ser128Leu)
Variation ID: 135943 Accession: VCV000135943.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 6002607 (GRCh38) [ NCBI UCSC ] 7: 6042238 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 2, 2016 May 1, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000535.7:c.383C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Ser128Leu missense NM_001322003.2:c.-23C>T 5 prime UTR NM_001322004.2:c.-23C>T 5 prime UTR NM_001322005.2:c.-23C>T 5 prime UTR NM_001322006.2:c.383C>T NP_001308935.1:p.Ser128Leu missense NM_001322007.2:c.65C>T NP_001308936.1:p.Ser22Leu missense NM_001322008.2:c.65C>T NP_001308937.1:p.Ser22Leu missense NM_001322009.2:c.-23C>T 5 prime UTR NM_001322010.2:c.-23C>T 5 prime UTR NM_001322011.2:c.-502C>T 5 prime UTR NM_001322012.2:c.-502C>T 5 prime UTR NM_001322013.2:c.-23C>T 5 prime UTR NM_001322014.2:c.383C>T NP_001308943.1:p.Ser128Leu missense NM_001322015.2:c.74C>T NP_001308944.1:p.Ser25Leu missense NR_136154.1:n.470C>T non-coding transcript variant NC_000007.14:g.6002607G>A NC_000007.13:g.6042238G>A NG_008466.1:g.11500C>T LRG_161:g.11500C>T LRG_161t1:c.383C>T - Protein change
- S128L, S25L, S22L
- Other names
- p.S128L:TCG>TTG
- p.Ser128Leu
- Canonical SPDI
- NC_000007.14:6002606:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00100 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00051
Exome Aggregation Consortium (ExAC) 0.00076
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00100
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00169
The Genome Aggregation Database (gnomAD) 0.00177
Trans-Omics for Precision Medicine (TOPMed) 0.00178
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 | ||
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HI score
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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. |
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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
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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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Jun 23, 2021 | RCV000128980.20 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000200993.24 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Dec 28, 2022 | RCV000587673.25 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2023 | RCV000662720.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 1, 2018 | RCV000758689.11 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV001084082.15 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001093681.9 | |
Likely benign (1) |
no assertion criteria provided
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- | RCV001356925.9 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 22, 2022 | RCV003492544.1 |
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. |
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Likely benign
(-)
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criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000304735.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Likely benign
(Feb 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697367.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.383C>T variant affects a conserved nucleotide, resulting in amino acid change from Ser to Leu. 4/4 in-silico tools predict damaging outcome for … (more)
Variant summary: The c.383C>T variant affects a conserved nucleotide, resulting in amino acid change from Ser to Leu. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 92/121400 control chromosomes at a frequency of 0.0007578, which is about 7 times of maximal expected frequency of a pathogenic allele (0.0001136), suggesting this variant is benign. Sequence alignment suggests alleles identified in ExAC controls are unlikely from PMS2 pseudogenes. In addition, multiple clinical laboratories/literature classified this variant as benign/likely benign/polymorphisms. Taken together, this variant was classified as likely benign. (less)
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Uncertain significance
(Sep 11, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000333808.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely benign
(Jun 23, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002530338.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Nov 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239598.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Uncertain significance
(Dec 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473154.2
First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024 |
Comment:
The PMS2 c.383C>T; p.Ser128Leu variant (rs116373169) is reported in the literature in an individual with suspected Lynch syndrome, although its clinical significance in this individual … (more)
The PMS2 c.383C>T; p.Ser128Leu variant (rs116373169) is reported in the literature in an individual with suspected Lynch syndrome, although its clinical significance in this individual was uncertain (Borras 2017). This variant is found in the African population with an allele frequency of 0.5% (136/24972 alleles, including 1 homozygote) in the Genome Aggregation Database, and it is reported as benign/likely benign by multiple laboratories in ClinVar (Variation ID: 135943). The serine at codon 128 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.413). Our laboratory has identified this variant in an individual who also carried a pathogenic truncating PMS2 variant. Although the evidence suggests this variant may be likely benign, there is currently insufficient information to classify with certainty. Therefore, based on available information, the clinical significance of this variant is uncertain at this time. References: Borras E et al. In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation. Cancer Prev Res (Phila). 2017 Oct;10(10):580-587. PMID: 28765196. (less)
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Benign
(Jun 23, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000596471.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Aug 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000785474.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Uncertain significance
(May 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: yes
Allele origin:
somatic
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000887461.1
First in ClinVar: Mar 11, 2019 Last updated: Mar 11, 2019 |
Comment:
PMS2 NM_000535.5:c.383C>T has a 14.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated … (more)
PMS2 NM_000535.5:c.383C>T has a 14.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214. (less)
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Likely benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001137327.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Oct 28, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000686199.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
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Likely benign
(Sep 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000211588.13
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 31433215, 28211887, 28765196, 28873162, 27930734, 20205264)
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Benign
(Apr 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004019783.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence … (more)
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. (less)
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Uncertain significance
(Mar 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004223992.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Number of individuals with the variant: 9
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Benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000166385.14
First in ClinVar: Jun 16, 2014 Last updated: Feb 20, 2024 |
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Likely benign
(Dec 26, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000172866.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Benign
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004025130.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Likely benign
(Sep 29, 2017)
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no assertion criteria provided
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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True Health Diagnostics
Accession: SCV000788115.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome 1
Affected status: no
Allele origin:
germline
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Ding PR Lab, Sun Yat-sen University Cancer Center
Accession: SCV001250862.1
First in ClinVar: May 19, 2020 Last updated: May 19, 2020 |
Age: 20-29 years
Sex: male
Geographic origin: China
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552219.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PMS2 p.Ser128Leu variant was identified in 1 of 290 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome (Vaughn 2010). The variant … (more)
The PMS2 p.Ser128Leu variant was identified in 1 of 290 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome (Vaughn 2010). The variant was also identified in dbSNP (ID: rs116373169) as "With other allele", ClinVar (classified as benign by Invitae and one other submitter; as likely benign by Ambry Genetics, GeneDx, and five other submitters; and as uncertain significance by one submitter), Cosmic (1x in skin tissue), and MutDB. The variant was not identified in COGR, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors database. The variant was identified in control databases in 188 of 276898 chromosomes (1 homozygous) at a frequency of 0.0007, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 134 of 24038 chromosomes (freq: 0.006), Latino in 3 of 34420 chromosomes (freq: 0.00009), European in 43 of 126388 chromosomes (freq: 0.0003), East Asian in 7 of 18870 chromosomes (freq: 0.0004), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Ashkenazi Jewish, or Finnish populations. The p.Ser128 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
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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 |
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In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation. | Borras E | Cancer prevention research (Philadelphia, Pa.) | 2017 | PMID: 28765196 |
A Comparative Analysis of Breast and Ovarian Cancer-related Gene Mutations in Canadian and Saudi Arabian Patients with Breast Cancer. | Amemiya Y | Anticancer research | 2015 | PMID: 25964535 |
FANCJ localization by mismatch repair is vital to maintain genomic integrity after UV irradiation. | Guillemette S | Cancer research | 2014 | PMID: 24351291 |
DNA repair genes are selectively mutated in diffuse large B cell lymphomas. | de Miranda NF | The Journal of experimental medicine | 2013 | PMID: 23960188 |
Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. | Vaughn CP | Human mutation | 2010 | PMID: 20205264 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PMS2 | - | - | - | - |
Text-mined citations for rs116373169 ...
HelpRecord last updated Jun 02, 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.