NM_000535.7(PMS2):c.1831dup (p.Ile611fs) AND Lynch syndrome
- Germline classification:
- Pathogenic (8 submissions)
- Last evaluated:
- Sep 5, 2013
- Review status:
- 3 stars out of maximum of 4 starsreviewed by expert panel
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000076830.20
Allele description [Variation Report for NM_000535.7(PMS2):c.1831dup (p.Ile611fs)]
NM_000535.7(PMS2):c.1831dup (p.Ile611fs)
- Gene:
- PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]
- Variant type:
- Duplication
- Cytogenetic location:
- 7p22.1
- Genomic location:
- Preferred name:
- NM_000535.7(PMS2):c.1831dup (p.Ile611fs)
- Other names:
- p.Ile611AsnfsX2
- HGVS:
- NC_000007.13:g.6026564_6026565insT
- NC_000007.14:g.5986937dup
- NG_008466.1:g.27173dup
- NM_000535.7:c.1831dupMANE SELECT
- NM_001322003.2:c.1426dup
- NM_001322004.2:c.1426dup
- NM_001322005.2:c.1426dup
- NM_001322006.2:c.1675dup
- NM_001322007.2:c.1513dup
- NM_001322008.2:c.1513dup
- NM_001322009.2:c.1426dup
- NM_001322010.2:c.1270dup
- NM_001322011.2:c.898dup
- NM_001322012.2:c.898dup
- NM_001322013.2:c.1258dup
- NM_001322014.2:c.1831dup
- NM_001322015.2:c.1522dup
- NP_000526.2:p.Ile611fs
- NP_001308932.1:p.Ile476fs
- NP_001308933.1:p.Ile476fs
- NP_001308934.1:p.Ile476fs
- NP_001308935.1:p.Ile559fs
- NP_001308936.1:p.Ile505fs
- NP_001308937.1:p.Ile505fs
- NP_001308938.1:p.Ile476fs
- NP_001308939.1:p.Ile424fs
- NP_001308940.1:p.Ile300fs
- NP_001308941.1:p.Ile300fs
- NP_001308942.1:p.Ile420fs
- NP_001308943.1:p.Ile611fs
- NP_001308944.1:p.Ile508fs
- LRG_161:g.27173dup
- NC_000007.13:g.6026564_6026565insT
- NC_000007.13:g.6026565dupT
- NC_000007.13:g.6026568dup
- NC_000007.13:g.6026568dup
- NM_000535.5:c.1831dupA
- NM_000535.6:c.1831dup
- NM_000535.6:c.1831dupA
- NM_000535.7:c.1831dupAMANE SELECT
- NR_136154.1:n.1918dup
- p.I611Nfs*2
- p.Ile611Asnfs*2
This HGVS expression did not pass validation- Protein change:
- I300fs
- Links:
- dbSNP: rs63750250
- NCBI 1000 Genomes Browser:
- rs63750250
- Molecular consequence:
- NM_000535.7:c.1831dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001322003.2:c.1426dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001322004.2:c.1426dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001322005.2:c.1426dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001322006.2:c.1675dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001322007.2:c.1513dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001322008.2:c.1513dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001322009.2:c.1426dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001322010.2:c.1270dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001322011.2:c.898dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001322012.2:c.898dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001322013.2:c.1258dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001322014.2:c.1831dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001322015.2:c.1522dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NR_136154.1:n.1918dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
- Observations:
- 1
Condition(s)
- Name:
- Lynch syndrome
- Identifiers:
- MONDO: MONDO:0005835; MedGen: C4552100
Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000108317 | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | reviewed by expert panel (Guidelines v1.9) | Pathogenic (Sep 5, 2013) | germline | research | |
| SCV000592940 | Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | germline | clinical testing | |
| SCV000697314 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (Aug 29, 2016) | germline | clinical testing | PubMed (6) LabCorp Variant Classification Summary - May 2015.docx, |
| SCV000711443 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | criteria provided, single submitter (LMM Criteria) | Pathogenic (Apr 19, 2019) | germline | clinical testing | |
| SCV000840125 | GenomeConnect, ClinGen | no classification provided | not provided | unknown | phenotyping only | |
| SCV000853184 | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | criteria provided, single submitter (St. Jude Assertion Criteria 2020) | Pathogenic (Sep 30, 2020) | germline | clinical testing | |
| SCV002061241 | DASA | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jan 5, 2022) | germline | clinical testing | |
| SCV004844126 | All of Us Research Program, National Institutes of Health | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Dec 13, 2023) | germline | clinical testing |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | germline | yes | 1 | not provided | not provided | not provided | not provided | clinical testing |
| not provided | germline | unknown | 6 | 1 | not provided | 108544 | not provided | clinical testing, research |
| Caucasians MedGen:C0043157 | unknown | yes | not provided | not provided | not provided | not provided | not provided | phenotyping only |
Citations
PubMed
Pagin A, Zerimech F, Leclerc J, Wacrenier A, Lejeune S, Descarpentries C, Escande F, Porchet N, Buisine MP.
Br J Cancer. 2013 May 28;108(10):2079-87. doi: 10.1038/bjc.2013.213. Epub 2013 May 7.
- PMID:
- 23652311
- PMCID:
- PMC3670492
Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.
Lavoine N, Colas C, Muleris M, Bodo S, Duval A, Entz-Werle N, Coulet F, Cabaret O, Andreiuolo F, Charpy C, Sebille G, Wang Q, Lejeune S, Buisine MP, Leroux D, Couillault G, Leverger G, Fricker JP, Guimbaud R, Mathieu-Dramard M, Jedraszak G, Cohen-Hagenauer O, et al.
J Med Genet. 2015 Nov;52(11):770-8. doi: 10.1136/jmedgenet-2015-103299. Epub 2015 Aug 28. Review.
- PMID:
- 26318770
Details of each submission
From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000108317.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | research | not provided |
Description
Coding sequence variation resulting in a stop codon
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592940.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697314.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (6) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711443.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (6) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | 1 | not provided | 1 | not provided | |
From GenomeConnect, ClinGen, SCV000840125.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | Caucasians MedGen:C0043157 | not provided | not provided | not provided | phenotyping only | not provided |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | yes | not provided | not provided | validation | not provided | not provided | not provided | not provided | |
From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV000853184.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From DASA, SCV002061241.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (9) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
From All of Us Research Program, National Institutes of Health, SCV004844126.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 5 | not provided | not provided | clinical testing | PubMed (14) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | 108544 | not provided | not provided | 5 | not provided | not provided | not provided | |
Last Updated: Oct 20, 2024