NM_000535.7(PMS2):c.2174+1G>A AND Lynch syndrome
- Germline classification:
- Pathogenic (3 submissions)
- Last evaluated:
- Mar 14, 2014
- 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:
- RCV000076844.11
Allele description [Variation Report for NM_000535.7(PMS2):c.2174+1G>A]
NM_000535.7(PMS2):c.2174+1G>A
- Gene:
- PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]
- Variant type:
- single nucleotide variant
- Cytogenetic location:
- 7p22.1
- Genomic location:
- Preferred name:
- NM_000535.7(PMS2):c.2174+1G>A
- Other names:
- IVS12+1G>A
- HGVS:
- NC_000007.14:g.5982823C>T
- NG_008466.1:g.31284G>A
- NM_000535.7:c.2174+1G>AMANE SELECT
- NM_001322003.2:c.1769+1G>A
- NM_001322004.2:c.1769+1G>A
- NM_001322005.2:c.1769+1G>A
- NM_001322006.2:c.2018+1G>A
- NM_001322007.2:c.1856+1G>A
- NM_001322008.2:c.1856+1G>A
- NM_001322009.2:c.1769+1G>A
- NM_001322010.2:c.1613+1G>A
- NM_001322011.2:c.1241+1G>A
- NM_001322012.2:c.1241+1G>A
- NM_001322013.2:c.1601+1G>A
- NM_001322014.2:c.2174+1G>A
- NM_001322015.2:c.1865+1G>A
- NM_001406866.1:c.2360+1G>A
- NM_001406868.1:c.2198+1G>A
- NM_001406869.1:c.2066+1G>A
- NM_001406870.1:c.2018+1G>A
- NM_001406871.1:c.2174+1G>A
- NM_001406872.1:c.2006+3936G>A
- NM_001406873.1:c.1976+1G>A
- NM_001406874.1:c.2006+1G>A
- NM_001406875.1:c.1865+1G>A
- NM_001406876.1:c.1856+1G>A
- NM_001406877.1:c.1865+1G>A
- NM_001406878.1:c.1865+1G>A
- NM_001406879.1:c.1865+1G>A
- NM_001406880.1:c.1865+1G>A
- NM_001406881.1:c.1865+1G>A
- NM_001406882.1:c.1865+1G>A
- NM_001406883.1:c.1856+1G>A
- NM_001406884.1:c.1850+1G>A
- NM_001406885.1:c.1838+1G>A
- NM_001406886.1:c.1808+1G>A
- NM_001406887.1:c.1769+1G>A
- NM_001406888.1:c.1769+1G>A
- NM_001406889.1:c.1769+1G>A
- NM_001406890.1:c.1769+1G>A
- NM_001406891.1:c.1769+1G>A
- NM_001406892.1:c.1769+1G>A
- NM_001406893.1:c.1769+1G>A
- NM_001406894.1:c.1769+1G>A
- NM_001406895.1:c.1769+1G>A
- NM_001406896.1:c.1769+1G>A
- NM_001406897.1:c.1769+1G>A
- NM_001406898.1:c.1769+1G>A
- NM_001406899.1:c.1769+1G>A
- NM_001406900.1:c.1709+1G>A
- NM_001406901.1:c.1700+1G>A
- NM_001406902.1:c.1700+1G>A
- NM_001406903.1:c.1688+3936G>A
- NM_001406904.1:c.1661+1G>A
- NM_001406905.1:c.1661+1G>A
- NM_001406906.1:c.1613+1G>A
- NM_001406907.1:c.1613+1G>A
- NM_001406908.1:c.1601+3936G>A
- NM_001406909.1:c.1601+1G>A
- NM_001406910.1:c.1601+3936G>A
- NM_001406911.1:c.1403+1G>A
- NM_001406912.1:c.971+1G>A
- LRG_161t1:c.2174+1G>A
- LRG_161:g.31284G>A
- NC_000007.13:g.6022454C>T
- NM_000535.5:c.2174+1G>A
- NM_000535.6:c.2174+1G>A
This HGVS expression did not pass validation- Links:
- dbSNP: rs267608172
- NCBI 1000 Genomes Browser:
- rs267608172
- Molecular consequence:
- NM_001406872.1:c.2006+3936G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406903.1:c.1688+3936G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406908.1:c.1601+3936G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406910.1:c.1601+3936G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_000535.7:c.2174+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001322003.2:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001322004.2:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001322005.2:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001322006.2:c.2018+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001322007.2:c.1856+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001322008.2:c.1856+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001322009.2:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001322010.2:c.1613+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001322011.2:c.1241+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001322012.2:c.1241+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001322013.2:c.1601+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001322014.2:c.2174+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001322015.2:c.1865+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406866.1:c.2360+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406868.1:c.2198+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406869.1:c.2066+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406870.1:c.2018+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406871.1:c.2174+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406873.1:c.1976+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406874.1:c.2006+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406875.1:c.1865+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406876.1:c.1856+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406877.1:c.1865+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406878.1:c.1865+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406879.1:c.1865+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406880.1:c.1865+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406881.1:c.1865+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406882.1:c.1865+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406883.1:c.1856+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406884.1:c.1850+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406885.1:c.1838+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406886.1:c.1808+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406887.1:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406888.1:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406889.1:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406890.1:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406891.1:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406892.1:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406893.1:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406894.1:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406895.1:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406896.1:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406897.1:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406898.1:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406899.1:c.1769+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406900.1:c.1709+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406901.1:c.1700+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406902.1:c.1700+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406904.1:c.1661+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406905.1:c.1661+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406906.1:c.1613+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406907.1:c.1613+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406909.1:c.1601+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406911.1:c.1403+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406912.1:c.971+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
- Functional consequence:
- sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071] - Comment(s)
- Intron inclusion between exons 12 & 13, based on review of RNA-seq in MOLT-3 cancer cell line which has PMS2 NM_000535.5:c.2174+1G>A variant.
- Observations:
- 1
Condition(s)
- Name:
- Lynch syndrome
- Identifiers:
- MONDO: MONDO:0005835; MedGen: C4552100
-
Homo sapiens p21 (RAC1) activated kinase 3 (PAK3), transcript variant 14, non-co...
Homo sapiens p21 (RAC1) activated kinase 3 (PAK3), transcript variant 14, non-coding RNAgi|1024336737|ref|NR_136744.1|Nucleotide
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See more...Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000108333 | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | reviewed by expert panel (Guidelines v1.9) | Pathogenic (Mar 14, 2014) | germline | research | |
| SCV000271439 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | criteria provided, single submitter (LMM Criteria) | Pathogenic (Apr 19, 2019) | germline | clinical testing | |
| SCV000697333 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (May 21, 2018) | germline | clinical testing |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | germline | unknown | 1 | 1 | not provided | not provided | not provided | clinical testing, research |
Citations
PubMed
Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S.
Gastroenterology. 2015 Sep;149(3):604-13.e20. doi: 10.1053/j.gastro.2015.05.006. Epub 2015 May 14.
- PMID:
- 25980754
- PMCID:
- PMC4550537
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.
Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, Hua Y, Gueroussov S, Najafabadi HS, Hughes TR, Morris Q, Barash Y, Krainer AR, Jojic N, Scherer SW, Blencowe BJ, Frey BJ.
Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.
- PMID:
- 25525159
- PMCID:
- PMC4362528
Details of each submission
From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000108333.4
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | research | not provided |
Description
Interrupts canonical donor splice site
| # | 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, SCV000271439.4
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (6) |
Description
The c.2174+1G>A variant in PMS2 has been reported in 1 heterozygous individual with PMS2-associated cancers, and in 1 compound heterozygous and 1 homozygous individual with constitutional mismatch repair deficiency (Senter 2008, Herkert 2011). It segregated in a compound heterozygous state with disease in one affect sibling (Herkert 2011). It has also has been identified in 1/30070 of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies provide some evidence that the c.2174+1G>A variant may impact the protein (Van Der Klift, 2015). In addition, it was classified as Pathogenic on April 16, 2014 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108333.3). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based. ACMG/AMP criteria applied: PM2, PS4_Supporting, 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697333.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (5) |
Description
Variant summary: PMS2 c.2174+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. RNA analysis was performed to study the effect of c.2174+1G>A on mRNA splicing and to confirm that this mutation is located in PMS2 and not in its highly homologous pseudogene PMS2CL. The variant allele was found at a frequency of 1.7e-05 in 239230 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (1.7e-05 vs 0.00011), allowing no conclusion about variant significance. c.2174+1G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome and features of CMMRD. Specifically, the variant has been cited in multiple patients in both heterozygous, compound heterozygous (in trans with a second pathogenic PMS2 variant), and homozygous state, several of whom have loss of PMS2 via IHC. Carrying two MMR mutations in PMS2 in trans has been associated with constitutional mismatch repair-deficiency, which is characterized by colonic polyposis and hematologic, brain and gastrointestinal malignancies, as well as neurofribromas, which present at a young age and thus both mutations may be explaining the phenotype in the individuals reported. The variant alone was found in unaffected parents of probands, further supporting the idea that the variant is involved in constitutional mismatch repair-deficiency. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, but does not provide convincing conclusions about the variant effect. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 | |
Last Updated: Aug 4, 2024