NM_000535.7(PMS2):c.251-20T>G AND not specified

Clinical significance:Likely benign (Last evaluated: Jul 14, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000535.7(PMS2):c.251-20T>G]


PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
Other names:
  • NC_000007.14:g.6003812A>C
  • NG_008466.1:g.10295T>G
  • NM_000535.7:c.251-20T>GMANE SELECT
  • NM_001322003.2:c.-155-20T>G
  • NM_001322004.2:c.-155-20T>G
  • NM_001322005.2:c.-155-20T>G
  • NM_001322006.2:c.251-20T>G
  • NM_001322007.1:c.35+160T>G
  • NM_001322008.2:c.35+160T>G
  • NM_001322009.2:c.-155-20T>G
  • NM_001322010.2:c.-155-20T>G
  • NM_001322011.2:c.-634-20T>G
  • NM_001322012.2:c.-634-20T>G
  • NM_001322013.2:c.-155-20T>G
  • NM_001322014.2:c.251-20T>G
  • NM_001322015.2:c.-234-20T>G
  • LRG_161t1:c.251-20T>G
  • LRG_161:g.10295T>G
  • NC_000007.13:g.6043443A>C
  • NM_000535.5:c.251-20T>G
  • NM_000535.6:c.251-20T>G
dbSNP: rs149343081
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000535.7:c.251-20T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322003.2:c.-155-20T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322004.2:c.-155-20T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322005.2:c.-155-20T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322006.2:c.251-20T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322007.1:c.35+160T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322008.2:c.35+160T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322009.2:c.-155-20T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322010.2:c.-155-20T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322011.2:c.-634-20T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322012.2:c.-634-20T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322013.2:c.-155-20T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322014.2:c.251-20T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322015.2:c.-234-20T>G - intron variant - [Sequence Ontology: SO:0001627]


MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000149598GeneDxcriteria provided, single submitter
Likely benign
(Nov 29, 2017)
germlineclinical testing

Citation Link,

SCV000918046Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(Jul 14, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000149598.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918046.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


Variant summary: PMS2 c.251-20T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00081 in 246010 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 24- fold the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. This data must be interpreted with caution, however, because the technology used in this data set is not able to rule out pseudogene interference. Due to the presence of multiple pseudogenes with PMS2, the population frequency was not used for scoring this variant. To our knowledge, no occurrence of c.251-20T>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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

Last Updated: Sep 6, 2021

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