Coding sequence variation resulting in a stop codon
ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.1831dup (p.Ile611fs)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Sep 2013 by
International …
for
Lynch Syndrome
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.1831dup (p.Ile611fs)
Variation ID: 91317 Accession: VCV000091317.73
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 5986933-5986934 (GRCh38) [ NCBI UCSC ] 7: 6026564-6026565 (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 Jun 9, 2014 Oct 20, 2024 Sep 5, 2013 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000535.7:c.1831dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Ile611fs frameshift NM_000535.7:c.1831dupA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000535.5:c.1831dupA NM_000535.6:c.1831dupA NM_001322003.2:c.1426dup NP_001308932.1:p.Ile476fs frameshift NM_001322004.2:c.1426dup NP_001308933.1:p.Ile476fs frameshift NM_001322005.2:c.1426dup NP_001308934.1:p.Ile476fs frameshift NM_001322006.2:c.1675dup NP_001308935.1:p.Ile559fs frameshift NM_001322007.2:c.1513dup NP_001308936.1:p.Ile505fs frameshift NM_001322008.2:c.1513dup NP_001308937.1:p.Ile505fs frameshift NM_001322009.2:c.1426dup NP_001308938.1:p.Ile476fs frameshift NM_001322010.2:c.1270dup NP_001308939.1:p.Ile424fs frameshift NM_001322011.2:c.898dup NP_001308940.1:p.Ile300fs frameshift NM_001322012.2:c.898dup NP_001308941.1:p.Ile300fs frameshift NM_001322013.2:c.1258dup NP_001308942.1:p.Ile420fs frameshift NM_001322014.2:c.1831dup NP_001308943.1:p.Ile611fs frameshift NM_001322015.2:c.1522dup NP_001308944.1:p.Ile508fs frameshift NR_136154.1:n.1918dup non-coding transcript variant NC_000007.14:g.5986937dup NC_000007.13:g.6026568dup NG_008466.1:g.27173dup LRG_161:g.27173dup - Protein change
- I476fs, I505fs, I508fs, I611fs, I300fs, I420fs, I424fs, I559fs
- Other names
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p.Ile611AsnfsX2
- Canonical SPDI
- NC_000007.14:5986933:TTTT:TTTTT
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
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. |
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| 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. |
|---|---|---|---|---|
| Pathogenic (8) |
reviewed by expert panel
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Sep 5, 2013 | RCV000076830.20 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 10, 2023 | RCV000115666.15 | |
| not provided (1) |
no classification provided
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Sep 19, 2013 | RCV000121837.6 | |
| Pathogenic (1) |
no assertion criteria provided
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Jul 24, 2014 | RCV000144653.2 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Aug 10, 2022 | RCV000258972.40 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 30, 2024 | RCV000524450.11 | |
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Feb 22, 2024 | RCV000851295.9 | |
| Pathogenic (1) |
no assertion criteria provided
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May 6, 2020 | RCV001254932.3 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Sep 05, 2013)
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reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000108317.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
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Comment:
Coding sequence variation resulting in a stop codon
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Pathogenic
(Sep 13, 2018)
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criteria provided, single submitter
Method: research
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Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI_GT
Accession: SCV000993578.1 First in ClinVar: Oct 01, 2019 Last updated: Oct 01, 2019 |
Number of individuals with the variant: 1
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Likely pathogenic
(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: SCV001137285.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
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Pathogenic
(Apr 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711443.3
First in ClinVar: Apr 09, 2018 Last updated: Jul 06, 2020 |
Comment:
The p.Ile611AsnfsX2 variant in PMS2 has been reported in 12 individuals with colorectal cancer including 10 with Lynch Syndrome (Bodo 2015, ten Broeke 2015, Lavoine … (more)
The p.Ile611AsnfsX2 variant in PMS2 has been reported in 12 individuals with colorectal cancer including 10 with Lynch Syndrome (Bodo 2015, ten Broeke 2015, Lavoine 2015, Goodenberger 2016, Susswein 2016), as well as in compound heterozygosity with another PMS2 variant in 2 individuals and 1 family member with constitutional MMR deficiency (Lavoine 2015, Bodo 2015, Susswein 2016). The p.Ile611AsnfsX2 variant has also been identified in 6/129170 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In addition, it has been classified as Pathogenic on September 5, 2013 by the InSiGHT expert panel (ClinVar SCV000108317.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 611 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the PMS2 gene is an established disease mechanism in colorectal cancer. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PM2,PS4_Moderate, PM3_Supporting, PVS1. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV000853184.2
First in ClinVar: Nov 25, 2018 Last updated: Oct 25, 2020 |
Comment:
This is a frameshift alteration in which coding nucleotide 1831 is duplicated. This is predicted to change an Isoleucine to an Aparagine at amino acid … (more)
This is a frameshift alteration in which coding nucleotide 1831 is duplicated. This is predicted to change an Isoleucine to an Aparagine at amino acid codon 611, shift the reading frame and result in a premature stop codon 2 amino acids downstream. Classification crieria: PVS1, PS3, PM2. (less)
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Pathogenic
(Jan 27, 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: SCV000149575.8
First in ClinVar: May 17, 2014 Last updated: Apr 17, 2019 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with Lynch syndrome-related cancers and tumor studies consistent with pathogenic variants in this gene (Truninger 2005, Tomsic 2013, Vaughn 2013, Yurgelun 2015, Rosty 2016, van der Klift 2016, Wang 2020); Observed with a pathogenic variant on the opposite allele (in trans) and in the homozygous state in patients with Constitutional Mismatch Repair Deficiency in the published literature (Alexander 2016, Cheyuo 2017, Hildreth 2018, Oshrine 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1828insA; This variant is associated with the following publications: (PMID: 29625052, 31992580, 31447099, 27037742, 30155321, 31189528, 28562508, 15887099, 25980754, 23012243, 26895986, 27435373, 30322717, 26318770, 26116798, 28874130, 24728327, 28514183, 25512458, 26110232, 26681312, 27017610, 23652311, 24728189, 25691505, 25856668, 22120844, 22577899, 24362816, 20205264, 18602922) (less)
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Pathogenic
(Jun 11, 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: SCV002530233.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The PMS2 c.1831dupA (p.I611NfsX2) variant has been reported in heterozygosity in numerous individuals with colorectal cancer (PMID: 27978560, 25856668, 25512458, 22120844, 18602922). Tumors found in … (more)
The PMS2 c.1831dupA (p.I611NfsX2) variant has been reported in heterozygosity in numerous individuals with colorectal cancer (PMID: 27978560, 25856668, 25512458, 22120844, 18602922). Tumors found in these patients exhibit loss of PMS2 protein expression (PMID: 25856668). The variant has also been reported as homozygous and compound heterozygous in numerous individuals with constitutional mismatch repair deficiency and loss of PMS2 in tumor and normal tissue (PMID: 26681312, 27037742, 30155321, 32773772). This variant causes a frameshift at amino acid 611 that results in premature termination 2 amino acids downstream. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). This variant was observed in 6/129170 chromosomes in the Non-Finnish European population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 91317). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: yes
Allele origin:
de novo
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Daryl Scott Lab, Baylor College of Medicine
Accession: SCV003915713.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
|
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Pathogenic
(Sep 21, 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: SCV004187675.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Pathogenic
(Aug 10, 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: SCV000691965.2
First in ClinVar: Feb 19, 2018 Last updated: Jan 26, 2024 |
Comment:
PP4, PP5, PM2, PVS1
Number of individuals with the variant: 1
|
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Pathogenic
(Jun 30, 2021)
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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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Revvity Omics, Revvity
Accession: SCV002018882.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 30, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000218784.13
First in ClinVar: Mar 29, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ile611Asnfs*2) in the PMS2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ile611Asnfs*2) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is present in population databases (rs63750250, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and constitutional mismatch repair deficiency syndrome and Lynch syndrome or suspected Lynch syndrome and ovarian cancer (PMID: 15887099, 18602922, 20205264, 22577899, 23012243, 24728189, 25512458, 25980754, 26318770). This variant is also known as 1828insA, 1831insA, and 1831_1832insA. ClinVar contains an entry for this variant (Variation ID: 91317). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004844126.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is also known … (more)
This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1828insA, 1831insA and c.1831_1832insA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected by/suspected of having Lynch syndrome (PMID: 18602922, 20205264, 22120844, 24728189, 25512458, 25856668, 26681312), in individuals affected by/suspected of having recessive constitutional DNA mismatch repair deficiency (CMMRD) syndrome (PMID: 26116798, 27017610, 27037742, 28562508, 32773772), and in a compound heterozygous individual affected with invasive adenocarcinoma (PMID: 30155321). This variant has been identified in 6/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 5
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Pathogenic
(Feb 22, 2024)
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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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Baylor Genetics
Accession: SCV004205441.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: yes
Allele origin:
germline
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592940.1 First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015 |
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Pathogenic
(Aug 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697314.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The PMS2 c.1831dupA (p.Ile611Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense … (more)
Variant summary: The PMS2 c.1831dupA (p.Ile611Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121354 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). It was reported in several cancer patients whose tumor had high MSI and lack of PMS2 staining based on IHC indicating pathogenicity. Additionally, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln637fs) suggesting the clinical importance of the C-termial region located downstream of the variant. Moreover, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jan 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002061241.1
First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022 |
Comment:
The c.1831dup;p.(Ile611Asnfs*2) is a null frameshift variant (NMD) in the PMS2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a … (more)
The c.1831dup;p.(Ile611Asnfs*2) is a null frameshift variant (NMD) in the PMS2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 91317; PMID: 23012243; 25512458; 25980754; 15887099; 18602922; 22577899; 20205264; 24728189) - PS4. This variant is not present in population databases (rs63750250, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Uruguay
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Pathogenic
(Aug 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: yes
Allele origin:
germline
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Human Genetics Bochum, Ruhr University Bochum
Accession: SCV004042794.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
ACMG criteria used to clasify this variant:PVS1, PS4, PM2_SUP
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Pathogenic
(May 29, 2020)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601829.5
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
Comment:
The PMS2 c.1831dup (p.Ile611Asnfs*2) variant alters the translational reading frame of the PMS2 mRNA and causes the premature termination of PMS2 protein synthesis. This variant … (more)
The PMS2 c.1831dup (p.Ile611Asnfs*2) variant alters the translational reading frame of the PMS2 mRNA and causes the premature termination of PMS2 protein synthesis. This variant has been reported in the published literature in several individuals and families affected with colorectal cancer (PMIDs: 15887099 (2005), 25980754 (2015), 27978560 (2016), 30155321 (2018)). The frequency of this variant in the general population, 0.000046 (6/129170 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(May 10, 2023)
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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: SCV000686165.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is also known … (more)
This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1828insA, 1831insA and c.1831_1832insA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected by/suspected of having Lynch syndrome (PMID: 18602922, 20205264, 22120844, 24728189, 25512458, 25856668, 26681312), in individuals affected by/suspected of having recessive constitutional DNA mismatch repair deficiency (CMMRD) syndrome (PMID: 26116798, 27017610, 27037742, 28562508, 32773772), and in a compound heterozygous individual affected with invasive adenocarcinoma (PMID: 30155321). This variant has been identified in 6/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Sep 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000172770.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.1831dupA pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a duplication of A at nucleotide position 1831, causing a … (more)
The c.1831dupA pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a duplication of A at nucleotide position 1831, causing a translational frameshift with a predicted alternate stop codon (p.I611Nfs*2). This mutation has been reported in multiple individuals with Lynch syndrome-associated cancers, many with tumors demonstrating microsatellite instability and/or loss of PMS2 by immunohistochemistry (Truninger K et al. Gastroenterology, 2005 May;128:1160-71; Senter L et al. Gastroenterology, 2008 Aug;135:419-28; Schofield L et al. Fam Cancer, 2012 Mar;11:1-6; Vaughn CP et al. Genes Chromosomes Cancer, 2013 Jan;52:107-12; Pagin A et al. Br J Cancer, 2013 May;108:2079-87; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Bodo S et al. Gastroenterology, 2015 Oct;149:1017-29.e3; Susswein LR et al. Genet Med, 2016 08;18:823-32; van der Klift HM et al. Hum Mutat, 2016 11;37:1162-1179; Cheyuo C et al. J. Pediatr. Hematol. Oncol., 2017 10;39:e381-e387; Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Wang Q et al. J Med Genet, 2020 07;57:487-499; Post CCB et al. J Natl Cancer Inst, 2021 Mar). In addition, this mutation has been identified as homozygous and in trans with additional PMS2 alterations in patients with constitutional mismatch repair deficiency (CMMRD) phenotypes (Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8; Alexander TB et al. Pediatr. Blood Cancer. 2016 Aug;63:1454-6; Mork ME et al. Fam. Cancer. 2016 Oct;15:587-91; Hildreth A et al. Case Rep. Genet. 2018 Jul;2018:8657823; Shuen AY et al. J Clin Oncol, 2019 02;37:461-470; Perez-Valencia JA et al. Genet Med, 2020 12;22:2081-2088; Oldfield LE et al. J Mol Diagn, 2021 02;23:242-252). This alteration has also been reported in 3/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 1828insA, c.1831_1832insA and 1831dup in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jun 01, 2020)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001371512.24
First in ClinVar: Jul 16, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jul 24, 2014)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome I
Affected status: unknown
Allele origin:
germline
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Pathway Genomics
Accession: SCV000189980.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
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Pathogenic
(May 06, 2020)
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no assertion criteria provided
Method: research
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Mismatch repair cancer syndrome 1
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Medical University Innsbruck
Accession: SCV001431022.1
First in ClinVar: Sep 05, 2020 Last updated: Sep 05, 2020 |
Comment:
This variant, NM_000535.6:c.1831dupA, was found in compound heterozygosity with the pathogenic variant NM_000535.6:c.(988+1_989-1)_(1144+1_1145-1)del. Sample UAB117 in Perez J et al, Genet Med (PMID: 32773772).
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001977681.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(Oct 16, 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: SCV000788111.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978562.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000086035.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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not provided
(-)
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no classification provided
Method: phenotyping only
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Lynch syndrome
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000840125.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Neoplasm of uterus (present)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Ethnicity/Population group: Caucasians MedGen:C0043157
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-08-10
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
The p.Ile611AsnfsX2 variant in PMS2 has been reported in 12 individuals with colorectal cancer including 10 with Lynch Syndrome (Bodo 2015, ten Broeke 2015, Lavoine 2015, Goodenberger 2016, Susswein 2016), as well as in compound heterozygosity with another PMS2 variant in 2 individuals and 1 family member with constitutional MMR deficiency (Lavoine 2015, Bodo 2015, Susswein 2016). The p.Ile611AsnfsX2 variant has also been identified in 6/129170 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In addition, it has been classified as Pathogenic on September 5, 2013 by the InSiGHT expert panel (ClinVar SCV000108317.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 611 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the PMS2 gene is an established disease mechanism in colorectal cancer. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PM2,PS4_Moderate, PM3_Supporting, PVS1.
Comment:
This is a frameshift alteration in which coding nucleotide 1831 is duplicated. This is predicted to change an Isoleucine to an Aparagine at amino acid codon 611, shift the reading frame and result in a premature stop codon 2 amino acids downstream. Classification crieria: PVS1, PS3, PM2.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with Lynch syndrome-related cancers and tumor studies consistent with pathogenic variants in this gene (Truninger 2005, Tomsic 2013, Vaughn 2013, Yurgelun 2015, Rosty 2016, van der Klift 2016, Wang 2020); Observed with a pathogenic variant on the opposite allele (in trans) and in the homozygous state in patients with Constitutional Mismatch Repair Deficiency in the published literature (Alexander 2016, Cheyuo 2017, Hildreth 2018, Oshrine 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1828insA; This variant is associated with the following publications: (PMID: 29625052, 31992580, 31447099, 27037742, 30155321, 31189528, 28562508, 15887099, 25980754, 23012243, 26895986, 27435373, 30322717, 26318770, 26116798, 28874130, 24728327, 28514183, 25512458, 26110232, 26681312, 27017610, 23652311, 24728189, 25691505, 25856668, 22120844, 22577899, 24362816, 20205264, 18602922)
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
PP4, PP5, PM2, PVS1
Comment:
This sequence change creates a premature translational stop signal (p.Ile611Asnfs*2) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is present in population databases (rs63750250, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and constitutional mismatch repair deficiency syndrome and Lynch syndrome or suspected Lynch syndrome and ovarian cancer (PMID: 15887099, 18602922, 20205264, 22577899, 23012243, 24728189, 25512458, 25980754, 26318770). This variant is also known as 1828insA, 1831insA, and 1831_1832insA. ClinVar contains an entry for this variant (Variation ID: 91317). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1828insA, 1831insA and c.1831_1832insA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected by/suspected of having Lynch syndrome (PMID: 18602922, 20205264, 22120844, 24728189, 25512458, 25856668, 26681312), in individuals affected by/suspected of having recessive constitutional DNA mismatch repair deficiency (CMMRD) syndrome (PMID: 26116798, 27017610, 27037742, 28562508, 32773772), and in a compound heterozygous individual affected with invasive adenocarcinoma (PMID: 30155321). This variant has been identified in 6/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Variant summary: The PMS2 c.1831dupA (p.Ile611Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121354 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). It was reported in several cancer patients whose tumor had high MSI and lack of PMS2 staining based on IHC indicating pathogenicity. Additionally, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln637fs) suggesting the clinical importance of the C-termial region located downstream of the variant. Moreover, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The c.1831dup;p.(Ile611Asnfs*2) is a null frameshift variant (NMD) in the PMS2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 91317; PMID: 23012243; 25512458; 25980754; 15887099; 18602922; 22577899; 20205264; 24728189) - PS4. This variant is not present in population databases (rs63750250, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
ACMG criteria used to clasify this variant:PVS1, PS4, PM2_SUP
Comment:
The PMS2 c.1831dup (p.Ile611Asnfs*2) variant alters the translational reading frame of the PMS2 mRNA and causes the premature termination of PMS2 protein synthesis. This variant has been reported in the published literature in several individuals and families affected with colorectal cancer (PMIDs: 15887099 (2005), 25980754 (2015), 27978560 (2016), 30155321 (2018)). The frequency of this variant in the general population, 0.000046 (6/129170 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Comment:
This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1828insA, 1831insA and c.1831_1832insA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected by/suspected of having Lynch syndrome (PMID: 18602922, 20205264, 22120844, 24728189, 25512458, 25856668, 26681312), in individuals affected by/suspected of having recessive constitutional DNA mismatch repair deficiency (CMMRD) syndrome (PMID: 26116798, 27017610, 27037742, 28562508, 32773772), and in a compound heterozygous individual affected with invasive adenocarcinoma (PMID: 30155321). This variant has been identified in 6/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The c.1831dupA pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a duplication of A at nucleotide position 1831, causing a translational frameshift with a predicted alternate stop codon (p.I611Nfs*2). This mutation has been reported in multiple individuals with Lynch syndrome-associated cancers, many with tumors demonstrating microsatellite instability and/or loss of PMS2 by immunohistochemistry (Truninger K et al. Gastroenterology, 2005 May;128:1160-71; Senter L et al. Gastroenterology, 2008 Aug;135:419-28; Schofield L et al. Fam Cancer, 2012 Mar;11:1-6; Vaughn CP et al. Genes Chromosomes Cancer, 2013 Jan;52:107-12; Pagin A et al. Br J Cancer, 2013 May;108:2079-87; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Bodo S et al. Gastroenterology, 2015 Oct;149:1017-29.e3; Susswein LR et al. Genet Med, 2016 08;18:823-32; van der Klift HM et al. Hum Mutat, 2016 11;37:1162-1179; Cheyuo C et al. J. Pediatr. Hematol. Oncol., 2017 10;39:e381-e387; Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Wang Q et al. J Med Genet, 2020 07;57:487-499; Post CCB et al. J Natl Cancer Inst, 2021 Mar). In addition, this mutation has been identified as homozygous and in trans with additional PMS2 alterations in patients with constitutional mismatch repair deficiency (CMMRD) phenotypes (Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8; Alexander TB et al. Pediatr. Blood Cancer. 2016 Aug;63:1454-6; Mork ME et al. Fam. Cancer. 2016 Oct;15:587-91; Hildreth A et al. Case Rep. Genet. 2018 Jul;2018:8657823; Shuen AY et al. J Clin Oncol, 2019 02;37:461-470; Perez-Valencia JA et al. Genet Med, 2020 12;22:2081-2088; Oldfield LE et al. J Mol Diagn, 2021 02;23:242-252). This alteration has also been reported in 3/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 1828insA, c.1831_1832insA and 1831dup in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant, NM_000535.6:c.1831dupA, was found in compound heterozygosity with the pathogenic variant NM_000535.6:c.(988+1_989-1)_(1144+1_1145-1)del. Sample UAB117 in Perez J et al, Genet Med (PMID: 32773772).
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
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:
Coding sequence variation resulting in a stop codon
Comment:
The p.Ile611AsnfsX2 variant in PMS2 has been reported in 12 individuals with colorectal cancer including 10 with Lynch Syndrome (Bodo 2015, ten Broeke 2015, Lavoine 2015, Goodenberger 2016, Susswein 2016), as well as in compound heterozygosity with another PMS2 variant in 2 individuals and 1 family member with constitutional MMR deficiency (Lavoine 2015, Bodo 2015, Susswein 2016). The p.Ile611AsnfsX2 variant has also been identified in 6/129170 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In addition, it has been classified as Pathogenic on September 5, 2013 by the InSiGHT expert panel (ClinVar SCV000108317.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 611 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the PMS2 gene is an established disease mechanism in colorectal cancer. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PM2,PS4_Moderate, PM3_Supporting, PVS1.
Comment:
This is a frameshift alteration in which coding nucleotide 1831 is duplicated. This is predicted to change an Isoleucine to an Aparagine at amino acid codon 611, shift the reading frame and result in a premature stop codon 2 amino acids downstream. Classification crieria: PVS1, PS3, PM2.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with Lynch syndrome-related cancers and tumor studies consistent with pathogenic variants in this gene (Truninger 2005, Tomsic 2013, Vaughn 2013, Yurgelun 2015, Rosty 2016, van der Klift 2016, Wang 2020); Observed with a pathogenic variant on the opposite allele (in trans) and in the homozygous state in patients with Constitutional Mismatch Repair Deficiency in the published literature (Alexander 2016, Cheyuo 2017, Hildreth 2018, Oshrine 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1828insA; This variant is associated with the following publications: (PMID: 29625052, 31992580, 31447099, 27037742, 30155321, 31189528, 28562508, 15887099, 25980754, 23012243, 26895986, 27435373, 30322717, 26318770, 26116798, 28874130, 24728327, 28514183, 25512458, 26110232, 26681312, 27017610, 23652311, 24728189, 25691505, 25856668, 22120844, 22577899, 24362816, 20205264, 18602922)
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
PP4, PP5, PM2, PVS1
Comment:
This sequence change creates a premature translational stop signal (p.Ile611Asnfs*2) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is present in population databases (rs63750250, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and constitutional mismatch repair deficiency syndrome and Lynch syndrome or suspected Lynch syndrome and ovarian cancer (PMID: 15887099, 18602922, 20205264, 22577899, 23012243, 24728189, 25512458, 25980754, 26318770). This variant is also known as 1828insA, 1831insA, and 1831_1832insA. ClinVar contains an entry for this variant (Variation ID: 91317). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1828insA, 1831insA and c.1831_1832insA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected by/suspected of having Lynch syndrome (PMID: 18602922, 20205264, 22120844, 24728189, 25512458, 25856668, 26681312), in individuals affected by/suspected of having recessive constitutional DNA mismatch repair deficiency (CMMRD) syndrome (PMID: 26116798, 27017610, 27037742, 28562508, 32773772), and in a compound heterozygous individual affected with invasive adenocarcinoma (PMID: 30155321). This variant has been identified in 6/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Variant summary: The PMS2 c.1831dupA (p.Ile611Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121354 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). It was reported in several cancer patients whose tumor had high MSI and lack of PMS2 staining based on IHC indicating pathogenicity. Additionally, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln637fs) suggesting the clinical importance of the C-termial region located downstream of the variant. Moreover, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The c.1831dup;p.(Ile611Asnfs*2) is a null frameshift variant (NMD) in the PMS2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 91317; PMID: 23012243; 25512458; 25980754; 15887099; 18602922; 22577899; 20205264; 24728189) - PS4. This variant is not present in population databases (rs63750250, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
ACMG criteria used to clasify this variant:PVS1, PS4, PM2_SUP
Comment:
The PMS2 c.1831dup (p.Ile611Asnfs*2) variant alters the translational reading frame of the PMS2 mRNA and causes the premature termination of PMS2 protein synthesis. This variant has been reported in the published literature in several individuals and families affected with colorectal cancer (PMIDs: 15887099 (2005), 25980754 (2015), 27978560 (2016), 30155321 (2018)). The frequency of this variant in the general population, 0.000046 (6/129170 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Comment:
This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1828insA, 1831insA and c.1831_1832insA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected by/suspected of having Lynch syndrome (PMID: 18602922, 20205264, 22120844, 24728189, 25512458, 25856668, 26681312), in individuals affected by/suspected of having recessive constitutional DNA mismatch repair deficiency (CMMRD) syndrome (PMID: 26116798, 27017610, 27037742, 28562508, 32773772), and in a compound heterozygous individual affected with invasive adenocarcinoma (PMID: 30155321). This variant has been identified in 6/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The c.1831dupA pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a duplication of A at nucleotide position 1831, causing a translational frameshift with a predicted alternate stop codon (p.I611Nfs*2). This mutation has been reported in multiple individuals with Lynch syndrome-associated cancers, many with tumors demonstrating microsatellite instability and/or loss of PMS2 by immunohistochemistry (Truninger K et al. Gastroenterology, 2005 May;128:1160-71; Senter L et al. Gastroenterology, 2008 Aug;135:419-28; Schofield L et al. Fam Cancer, 2012 Mar;11:1-6; Vaughn CP et al. Genes Chromosomes Cancer, 2013 Jan;52:107-12; Pagin A et al. Br J Cancer, 2013 May;108:2079-87; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Bodo S et al. Gastroenterology, 2015 Oct;149:1017-29.e3; Susswein LR et al. Genet Med, 2016 08;18:823-32; van der Klift HM et al. Hum Mutat, 2016 11;37:1162-1179; Cheyuo C et al. J. Pediatr. Hematol. Oncol., 2017 10;39:e381-e387; Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Wang Q et al. J Med Genet, 2020 07;57:487-499; Post CCB et al. J Natl Cancer Inst, 2021 Mar). In addition, this mutation has been identified as homozygous and in trans with additional PMS2 alterations in patients with constitutional mismatch repair deficiency (CMMRD) phenotypes (Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8; Alexander TB et al. Pediatr. Blood Cancer. 2016 Aug;63:1454-6; Mork ME et al. Fam. Cancer. 2016 Oct;15:587-91; Hildreth A et al. Case Rep. Genet. 2018 Jul;2018:8657823; Shuen AY et al. J Clin Oncol, 2019 02;37:461-470; Perez-Valencia JA et al. Genet Med, 2020 12;22:2081-2088; Oldfield LE et al. J Mol Diagn, 2021 02;23:242-252). This alteration has also been reported in 3/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 1828insA, c.1831_1832insA and 1831dup in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant, NM_000535.6:c.1831dupA, was found in compound heterozygosity with the pathogenic variant NM_000535.6:c.(988+1_989-1)_(1144+1_1145-1)del. Sample UAB117 in Perez J et al, Genet Med (PMID: 32773772).
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical exome sequencing efficacy and phenotypic expansions involving anomalous pulmonary venous return. | Huth EA | European journal of human genetics : EJHG | 2023 | PMID: 37673932 |
| Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer. | Post CCB | Journal of the National Cancer Institute | 2021 | PMID: 33693762 |
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| An Integrative DNA Sequencing and Methylation Panel to Assess Mismatch Repair Deficiency. | Oldfield LE | The Journal of molecular diagnostics : JMD | 2021 | PMID: 33259954 |
| Constitutional mismatch repair deficiency is the diagnosis in 0.41% of pathogenic NF1/SPRED1 variant negative children suspected of sporadic neurofibromatosis type 1. | Perez-Valencia JA | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32773772 |
| Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome. | Wang Q | Journal of medical genetics | 2020 | PMID: 31992580 |
| Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
| Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue. | Shuen AY | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2019 | PMID: 30608896 |
| Germline pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
| Biallelic Mismatch Repair Deficiency in an Adolescent Female. | Hildreth A | Case reports in genetics | 2018 | PMID: 30155321 |
| A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. | Rossi BM | BMC cancer | 2017 | PMID: 28874130 |
| Biallelic PMS2 Mutation and Heterozygous DICER1 Mutation Presenting as Constitutional Mismatch Repair Deficiency With Corpus Callosum Agenesis: Case Report and Review of Literature. | Cheyuo C | Journal of pediatric hematology/oncology | 2017 | PMID: 28562508 |
| Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. | Pearlman R | JAMA oncology | 2017 | PMID: 27978560 |
| 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 |
| Metachronous T-Lymphoblastic Lymphoma and Burkitt Lymphoma in a Child With Constitutional Mismatch Repair Deficiency Syndrome. | Alexander TB | Pediatric blood & cancer | 2016 | PMID: 27037742 |
| Identification of a novel PMS2 alteration c.505C>G (R169G) in trans with a PMS2 pathogenic mutation in a patient with constitutional mismatch repair deficiency. | Mork ME | Familial cancer | 2016 | PMID: 27017610 |
| Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
| PMS2 monoallelic mutation carriers: the known unknown. | Goodenberger ML | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 25856668 |
| Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. | Lavoine N | Journal of medical genetics | 2015 | PMID: 26318770 |
| Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents. | Bodo S | Gastroenterology | 2015 | PMID: 26116798 |
| Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
| 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 |
| Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
| The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. | Song H | Human molecular genetics | 2014 | PMID: 24728189 |
| 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 |
| Evaluation of a new panel of six mononucleotide repeat markers for the detection of DNA mismatch repair-deficient tumours. | Pagin A | British journal of cancer | 2013 | PMID: 23652311 |
| The frequency of previously undetectable deletions involving 3' Exons of the PMS2 gene. | Vaughn CP | Genes, chromosomes & cancer | 2013 | PMID: 23012243 |
| Recurrent and founder mutations in the PMS2 gene. | Tomsic J | Clinical genetics | 2013 | PMID: 22577899 |
| A state-wide population-based program for detection of lynch syndrome based upon immunohistochemical and molecular testing of colorectal tumours. | Schofield L | Familial cancer | 2012 | PMID: 22120844 |
| 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 |
| Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. | Vaughn CP | Human mutation | 2010 | PMID: 20205264 |
| The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. | Senter L | Gastroenterology | 2008 | PMID: 18602922 |
| Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. | Truninger K | Gastroenterology | 2005 | PMID: 15887099 |
| http://www.insight-database.org/classifications/index.html?gene=PMS2&variant=c.1831dup | - | - | - | - |
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Text-mined citations for rs63750250 ...
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Record last updated Oct 20, 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.