Comprehensive mismatch repair gene panel identifies variants in patients with Lynch‐like syndrome. Issue 8 (12th July 2019)

• Record Type: Journal Article
• Authors: Xavier, Alexandre; Olsen, Maren Fridtjofsen; Lavik, Liss A.; Johansen, Jostein; Singh, Ashish Kumar; Sjursen, Wenche; Scott, Rodney J.; Talseth‐Palmer, Bente A.
• Is Part Of: Molecular genetics & genomic medicine. Volume 7:Issue 8(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-07-12
• Subjects: Genetics -- germline mutation -- high‐throughput sequencing -- Lynch syndrome -- MMR gene panel; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.850
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Background: Lynch‐like syndrome (LLS) represents around 50% of the patients fulfilling the Amsterdam Criteria II/revised Bethesda Guidelines, characterized by a strong family history of Lynch Syndrome (LS) associated cancer, where a causative variant was not identified during genetic testing for LS. Methods: Using data extracted from a larger gene panel, we have analyzed next‐generation sequencing data from 22 mismatch repair (MMR) genes ( MSH3, PMS1, MLH3, EXO1, POLD1, POLD3 RFC1, RFC2, RFC3, RFC4, RFC5, PCNA, LIG1, RPA1, RPA2, RPA3, POLD2, POLD4, MLH1, MSH2, MSH6, and PMS2 ) in 274 LLS patients. Detected variants were annotated and filtered using ANNOVAR and FILTUS software. Results: Thirteen variants were revealed in MLH1, MSH2, and MSH6, all genes previously linked to LS. Five additional genes ( EXO1, POLD1, RFC1, RPA1, and MLH3 ) were found to harbor 11 variants of unknown significance in our sample cohort, two of them being frameshift variants. Conclusion: We have shown that other genes associated with the process of DNA MMR have a high probability of being associated with LLS families. These findings indicate that the spectrum of genes that should be tested when considering an entity like Lynch‐like syndrome should be expanded so that a more inclusive definition of this entity can be developed. Abstract : Twenty‐two mismatch repair (MMR) genes were sequenced in 274 Lynch‐Like Syndrome (LLS) patients. We have shown that non‐screened genes associated with the process of DNA MMR have a high probability of being associated with LLS families. Re‐testing the four know Lynch Syndrome (LS) genes in previously mutation negative LS patients with a more sensitive approach of next‐generation sequencing should be top priority for clinical laboratories testing for LS around the world.