PMS2 – Lynch syndrome–associated Ovarian Cancer

PMS2 encodes a key MutLα component in the DNA mismatch repair (MMR) pathway. Germline heterozygous loss‐of‐function variants in PMS2 cause Lynch syndrome, an autosomal dominant cancer predisposition syndrome with elevated risks of colorectal, endometrial, and ovarian cancers. Ovarian tumors arising in PMS2 carriers often exhibit MMR deficiency, microsatellite instability, and loss of PMS2 protein expression by immunohistochemistry.

Clinical Validity

Based on available data, the association between PMS2 and Lynch syndrome–associated ovarian cancer is classified as Limited by ClinGen criteria. Two unrelated ovarian cancer patients have been documented with pathogenic PMS2 germline variants: one in a high‐risk Manchester series (1/33 carriers) (PMID:32917768) and one in a prospective Ontario cohort (1/22 MMR‐deficient cases) (PMID:37940339). No formal segregation analyses in large pedigrees have been reported.

Genetic Evidence

Inheritance is autosomal dominant. Among women with ovarian cancer and suggestive personal or family history, constitutional testing identified pathogenic PMS2 variants in 2 probands to date. Tumors from these carriers uniformly show loss of PMS2 expression and high microsatellite instability. Variant spectrum in Lynch syndrome includes start‐loss PMS2:c.2T>A (p.Met1Lys) which abolishes translation initiation (PMID:21204794). No recurrent founder alleles have been described, and carrier frequency in unselected ovarian cohorts remains low (<1%).

Experimental Evidence

Functional studies in murine and cellular models confirm that PMS2 deficiency impairs DNA mismatch repair, increases spontaneous mutation rates, and alters apoptosis. Pms2–/– mice exhibit hypermutation in immunoglobulin genes and defective repair of tandem mispairs (PMID:9618520; PMID:10429667). Mutations in the conserved DQHA(X)2E(X)4E endonuclease motif of PMS2 (e.g. p.Glu705Lys) abrogate endonuclease activity and mismatch repair functions (PMID:17567544). The human PMS2(R20Q) polymorphic variant fails to activate p73-mediated apoptosis in response to cisplatin, implicating PMS2 in apoptotic signaling (PMID:18768816).

Integration & Clinical Utility

Heterozygous loss‐of‐function PMS2 variants confer a moderately increased lifetime risk of ovarian cancer within Lynch syndrome. Tumor screening by MMR immunohistochemistry and MSI testing should include PMS2. Positive MMR‐deficient ovarian tumors warrant germline PMS2 analysis as part of Lynch syndrome evaluation. Given limited proband numbers, further large familial studies are needed to refine ovarian penetrance.

Key Take-home: Germline PMS2 pathogenic variants, though rare, underpin Lynch syndrome–related ovarian cancers and justify routine MMR and germline testing to guide surveillance and risk‐reducing strategies.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1998 • Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2 PMID:9618520
• The Journal of experimental medicine • 1999 • Different mismatch repair deficiencies all have the same effects on somatic hypermutation: intact primary mechanism accompanied by secondary modifications PMID:10429667
• DNA Repair • 2007 • Mutations affecting a putative MutLα endonuclease motif impact multiple mismatch repair functions PMID:17567544
• Journal of medical genetics • 2021 • Assessment of mismatch repair deficiency in ovarian cancer PMID:32917768
• International journal of gynecological cancer : official journal of the International Gynecological Cancer Society • 2024 • Comprehensive molecular assessment of mismatch repair deficiency in Lynch associated ovarian cancers using next generation sequencing panel PMID:37940339
• Clinical genetics • 2011 • Pitfalls in molecular analysis for mismatch repair deficiency in a family with biallelic pms2 germline mutations PMID:21204794

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