NM_000535.7(PMS2):c.251-2A>T AND Lynch syndrome
- Germline classification:
- Pathogenic/Likely pathogenic (3 submissions)
- Last evaluated:
- Jan 22, 2024
- Review status:
- 2 stars out of maximum of 4 starscriteria provided, multiple submitters, no conflicts
- 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:
- RCV000205731.15
Allele description [Variation Report for NM_000535.7(PMS2):c.251-2A>T]
NM_000535.7(PMS2):c.251-2A>T
- 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.251-2A>T
- HGVS:
- NC_000007.14:g.6003794T>A
- NG_008466.1:g.10313A>T
- NM_000535.7:c.251-2A>TMANE SELECT
- NM_001322003.2:c.-155-2A>T
- NM_001322004.2:c.-155-2A>T
- NM_001322005.2:c.-155-2A>T
- NM_001322006.2:c.251-2A>T
- NM_001322007.2:c.35+178A>T
- NM_001322008.2:c.35+178A>T
- NM_001322009.2:c.-155-2A>T
- NM_001322010.2:c.-155-2A>T
- NM_001322011.2:c.-634-2A>T
- NM_001322012.2:c.-634-2A>T
- NM_001322013.2:c.-155-2A>T
- NM_001322014.2:c.251-2A>T
- NM_001322015.2:c.-234-2A>T
- NM_001406866.1:c.437-2A>T
- NM_001406868.1:c.273A>T
- NM_001406869.1:c.251-2A>T
- NM_001406870.1:c.251-2A>T
- NM_001406871.1:c.251-2A>T
- NM_001406872.1:c.251-2A>T
- NM_001406873.1:c.251-2A>T
- NM_001406874.1:c.251-2A>T
- NM_001406875.1:c.-234-2A>T
- NM_001406876.1:c.35+178A>T
- NM_001406877.1:c.-234-2A>T
- NM_001406878.1:c.-234-2A>T
- NM_001406879.1:c.-234-2A>T
- NM_001406880.1:c.-181-2A>T
- NM_001406881.1:c.-132+178A>T
- NM_001406882.1:c.-234-2A>T
- NM_001406883.1:c.35+178A>T
- NM_001406884.1:c.251-2A>T
- NM_001406885.1:c.250+178A>T
- NM_001406886.1:c.251-2A>T
- NM_001406887.1:c.-155-2A>T
- NM_001406888.1:c.-102-2A>T
- NM_001406889.1:c.-102-2A>T
- NM_001406890.1:c.-145-2A>T
- NM_001406891.1:c.-155-2A>T
- NM_001406892.1:c.-102-2A>T
- NM_001406893.1:c.-155-2A>T
- NM_001406894.1:c.-102-2A>T
- NM_001406895.1:c.-102-2A>T
- NM_001406896.1:c.-52-1158A>T
- NM_001406897.1:c.-155-2A>T
- NM_001406898.1:c.-155-2A>T
- NM_001406899.1:c.-102-2A>T
- NM_001406900.1:c.-132+178A>T
- NM_001406901.1:c.35+178A>T
- NM_001406902.1:c.35+178A>T
- NM_001406903.1:c.35+178A>T
- NM_001406904.1:c.-102-2A>T
- NM_001406905.1:c.-155-2A>T
- NM_001406906.1:c.-155-2A>T
- NM_001406907.1:c.-102-2A>T
- NM_001406908.1:c.-155-2A>T
- NM_001406909.1:c.-102-2A>T
- NM_001406910.1:c.-155-2A>T
- NM_001406911.1:c.-155-2A>T
- NM_001406912.1:c.251-2A>T
- NP_001393797.1:p.Ser91=
- LRG_161t1:c.251-2A>T
- LRG_161:g.10313A>T
- NC_000007.13:g.6043425T>A
- NM_000535.5:c.251-2A>T
- NM_000535.6:c.251-2A>T
This HGVS expression did not pass validation- Links:
- dbSNP: rs587779340
- NCBI 1000 Genomes Browser:
- rs587779340
- Molecular consequence:
- NM_001322007.2:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
- NM_001322008.2:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406876.1:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406881.1:c.-132+178A>T - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406883.1:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406885.1:c.250+178A>T - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406896.1:c.-52-1158A>T - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406900.1:c.-132+178A>T - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406901.1:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406902.1:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406903.1:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
- NM_000535.7:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001322003.2:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001322004.2:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001322005.2:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001322006.2:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001322009.2:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001322010.2:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001322011.2:c.-634-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001322012.2:c.-634-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001322013.2:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001322014.2:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001322015.2:c.-234-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406866.1:c.437-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406869.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406870.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406871.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406872.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406873.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406874.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406875.1:c.-234-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406877.1:c.-234-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406878.1:c.-234-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406879.1:c.-234-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406880.1:c.-181-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406882.1:c.-234-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406884.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406886.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406887.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406888.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406889.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406890.1:c.-145-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406891.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406892.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406893.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406894.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406895.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406897.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406898.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406899.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406904.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406905.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406906.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406907.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406908.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406909.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406910.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406911.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406912.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406868.1:c.273A>T - synonymous variant - [Sequence Ontology: SO:0001819]
- 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 |
---|---|---|---|---|---|---|
SCV000266117 | University of Washington Department of Laboratory Medicine, University of Washington | criteria provided, single submitter (Shirts et al. (Genet Med 2016)) | Likely pathogenic (Nov 20, 2015) | germline | clinical testing | |
SCV000967786 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | criteria provided, single submitter (LMM Criteria) | Pathogenic (Mar 9, 2018) | germline | clinical testing | |
SCV004814295 | All of Us Research Program, National Institutes of Health | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jan 22, 2024) | 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 | 1 | not provided | clinical testing |
not provided | germline | not provided | 1 | 1 | not provided | not provided | not provided | clinical testing |
not provided | germline | unknown | 2 | not provided | not provided | 108544 | not provided | clinical testing |
Citations
PubMed
Improving performance of multigene panels for genomic analysis of cancer predisposition.
Shirts BH, Casadei S, Jacobson AL, Lee MK, Gulsuner S, Bennett RL, Miller M, Hall SA, Hampel H, Hisama FM, Naylor LV, Goetsch C, Leppig K, Tait JF, Scroggins SM, Turner EH, Livingston R, Salipante SJ, King MC, Walsh T, Pritchard CC.
Genet Med. 2016 Oct;18(10):974-81. doi: 10.1038/gim.2015.212. Epub 2016 Feb 4.
- PMID:
- 26845104
Herkert JC, Niessen RC, Olderode-Berends MJ, Veenstra-Knol HE, Vos YJ, van der Klift HM, Scheenstra R, Tops CM, Karrenbeld A, Peters FT, Hofstra RM, Kleibeuker JH, Sijmons RH.
Eur J Cancer. 2011 May;47(7):965-82. doi: 10.1016/j.ejca.2011.01.013. Epub 2011 Mar 4. Review.
- PMID:
- 21376568
Details of each submission
From University of Washington Department of Laboratory Medicine, University of Washington, SCV000266117.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 1 | 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 | 1 | not provided | not provided | 1 | not provided | not provided | not provided |
From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967786.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (4) |
Description
The c.251-2A>T variant in PMS2 has been reported in one individual with suspecte d Lynch syndrome (Yurgelun 2015) and has also been reported by other clinical la boratories in ClinVar (Variation ID# 183893). Additionally, two other variants a t this position (c.251-2A>C, c.251A>G) have been reported in individuals with PM S2-related cancers (Herkert 2011, Senter 2008), one of which has also been class ified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108354.2). The c.251A>T variant has also been identified in 1/108456 European chromosomes by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org; dbSNP rs587779340). This frequency is low enough to be consistent with the frequency of Lynch syndrome in the general population. T his variant occurs in the invariant region (+/- 1,2) of the splice consensus seq uence and is predicted to cause altered splicing leading to an abnormal or absen t protein. Heterozygous loss of function of the PMS2 gene is an established dise ase mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal domi nant manner based upon predicted impact to the protein, very low frequency in th e general population and the presence of a different pathogenic variant at the s ame position. ACMG/AMP criteria applied (Richards 2015): PVS1, PM5, PM2.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | not provided | not provided | not provided | not provided | 1 | not provided | 1 | not provided |
From All of Us Research Program, National Institutes of Health, SCV004814295.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 2 | not provided | not provided | clinical testing | PubMed (5) |
Description
This variant causes an A to T nucleotide substitution at the -2 position of intron 3 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals suspected of having Lynch syndrome or colorectal cancer with clinical features of Lynch syndrome (PMID: 25980754, 31992580), in individuals with ovarian cancer (PMID: 33881185) and oligodendroglioma (PMID: 35982947). This variant has been identified in 1/244282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c..251-2A>G and c.251-2A>C, are known to be disease-causing (ClinVar variation ID: 91345, 233781). 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 | 2 | not provided | not provided | not provided |
Last Updated: Oct 8, 2024