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A PMS2 non-canonical splicing site variant leads to aberrant splicing in a patient suspected for lynch syndrome

Ahmed Bouras1, Pierre Naibo2, Clémentine Legrand3

  • 1Laboratory of constitutional genetics for frequent cancers HCL-CLB, Centre Leon Berard, 69008, Lyon, France. ahmed.bouras@lyon.unicancer.fr.

Familial Cancer
|November 29, 2022
PubMed

Insights

A PMS2 gene variant, previously unknown significance, caused exon skipping and a truncated protein in an endometrial cancer patient. This highlights the need for RNA analysis in Lynch syndrome screening.

Area of Science:

  • Genetics
  • Molecular Biology
  • Oncology

Background:

  • Lynch syndrome (LS) is linked to DNA mismatch repair (MMR) gene variants, including PMS2.
  • Many intronic PMS2 variants outside canonical splice sites are classified as variants of unknown significance.
  • Assessing these variants is crucial for accurate LS diagnosis.

Observation:

  • An intronic PMS2 variant (c.251-5T>C) was identified in an endometrial cancer patient with microsatellite instability and loss of PMS2 expression.
  • RNA analysis was performed to investigate the functional impact of this intronic variant.
  • The patient was 82 years old and diagnosed with endometrial cancer.

Findings:

  • The intronic PMS2 variant (c.251-5T>C) caused complete skipping of exon 4.
  • This exon skipping resulted in the synthesis of a truncated PMS2 protein.
  • Functional RNA analysis revealed the pathogenic nature of a non-canonical intronic variant.

Implications:

  • Functional RNA analysis is essential for assessing non-canonical intronic variants in MMR genes.
  • Systematic evaluation of microsatellite instability (MSI) and MMR gene expression loss is important for LS screening in endometrial cancer patients.
  • This study underscores the clinical relevance of investigating intronic variants for Lynch syndrome diagnosis.
Keywords:
Endometrial cancerLynch syndromePMS2Splice variantdMMR

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