NM_000535.7(PMS2):c.251-2A>T AND Hereditary cancer-predisposing syndrome
- Germline classification:
- Pathogenic (2 submissions)
- Last evaluated:
- Jan 31, 2023
- 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:
- RCV000162757.6
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]
Condition(s)
- Name:
- Hereditary cancer-predisposing syndrome
- Synonyms:
- Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
- Identifiers:
- MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672
Assertion and evidence details
Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
---|---|---|---|---|---|---|
SCV000213233 | Ambry Genetics | criteria provided, single submitter (Ambry Variant Classification Scheme 2023) | Pathogenic (Jan 28, 2022) | germline | clinical testing | |
SCV004359698 | Color Diagnostics, LLC DBA Color Health | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jan 31, 2023) | germline | clinical testing |
Summary from all submissions
Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
---|---|---|---|---|---|---|---|---|
not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
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
Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome.
Wang Q, Leclerc J, Bougeard G, Olschwang S, Vasseur S, Cassinari K, Boidin D, Lefol C, Naïbo P, Frébourg T, Buisine MP, Baert-Desurmont S; French Consortium of Oncogenetic laboratories for colorectal cancers, Unicancer Cancer Genetic Group (GGC)..
J Med Genet. 2020 Jul;57(7):487-499. doi: 10.1136/jmedgenet-2019-106256. Epub 2020 Jan 28.
- PMID:
- 31992580
Details of each submission
From Ambry Genetics, SCV000213233.7
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (2) |
Description
The c.251-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides before coding exon 4 in the PMS2 gene. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). This alteration has also been identified in an individual diagnosed with colorectal cancer at 54. Immunohistochemistry of the tumor showed loss of expression of MSH6 and PMS2 (Wang Q et al. J Med Genet, 2020 07;57:487-499). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Two other alterations at this position (c.251-2A>G and c.251-2A>C) have been reported as pathogenic in Lynch syndrome and CMMR-D cohorts (Senter L et al. Gastroenterology. 2008 Aug;135:419-28; Niessen RC et al. Genes Chromosomes Cancer. 2009 Apr;48:322-9). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
# | 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 Color Diagnostics, LLC DBA Color Health, SCV004359698.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | 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, 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 | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
Last Updated: Jun 23, 2024