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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 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no 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
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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000213233Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jan 28, 2022) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004359698Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jan 31, 2023) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

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.

PubMed [citation]
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.

PubMed [citation]
PMID:
31992580
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000213233.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV004359698.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 23, 2024