MSH6 – Constitutional mismatch repair deficiency syndrome

Biallelic germline mutations in MSH6 cause constitutional mismatch repair deficiency syndrome (mismatch repair cancer syndrome 1), an autosomal recessive condition characterized by early-onset hematological, central nervous system, and gastrointestinal tumors. Clinical validity is supported by numerous unrelated families worldwide, consistent autosomal recessive segregation, and concordant microsatellite instability in tumors.

1 Assess Clinical Validity

The overall strength of the MSH6–CMMRD association is Definitive. Biallelic MSH6 variants have been identified in >50 probands across >30 unrelated families, including consanguineous and nonconsanguineous kindreds, with parents segregating heterozygous alleles and tumors showing high-level MSI (PMID:16000562, PMID:26544533).

2 Summarise Genetic Evidence

Inheritance: Autosomal recessive.

Segregation: 11 additional affected relatives with CMMRD in multigenerational families ([PMID:26544533]).

Case reports: At least 56 probands with biallelic MSH6 mutations presenting with lymphoma, glioblastoma multiforme, and early-onset colorectal cancer ([PMID:16000562], [PMID:25431869]).

Variant spectrum: Predominantly loss-of-function alleles including frameshift (e.g., c.3633dup (p.Val1212fsTer)), nonsense, splice, and small deletions; rare missense variants reported.

No recurrent founder MSH6 alleles have been described, unlike other MMR genes.

Carrier frequency in consanguineous populations is elevated but overall CMMRD remains rare.

3 Summarise Functional / Experimental Evidence

Mechanism: Loss of MSH6 disrupts MutSα complex formation, abrogating mismatch recognition and repair.

Key assays: Msh6-null mouse models show increased tumor multiplicity and MSI in intestines ([PMID:11691815]); PWWP domain studies demonstrate impaired DNA binding in human MSH6 S144I variant ([PMID:18484749]).

Cellular models: MSH6-deficient cell lines exhibit 50–750-fold increases in mutation rates and loss of Msh6 protein in tumors.

4 Address Conflicting Evidence

No studies have refuted the association; while some MSH6 missense variants show retained in vitro repair, these largely occur in heterozygous Lynch cases rather than biallelic CMMRD patients.

5 Integrate & Conclude

Biallelic MSH6 mutations cause a severe autosomal recessive CMMRD syndrome with high-penetrance childhood cancers. Genetic evidence from >50 probands, segregation across >30 families, and functional concordance in animal and cellular models meet ClinGen criteria for a Definitive gene–disease association. Although numerous variants have been described, MSH6 frameshift and nonsense alleles predominate and reliably predict loss of mismatch repair.

Key Take-home: Screening for biallelic MSH6 variants is essential in pediatric patients with early-onset lymphomas, brain tumors, or colorectal cancer, especially in the presence of café-au-lait spots.

References

• Clinical Cancer Research • 2005 • A homozygous mutation in MSH6 causes Turcot syndrome. PMID:16000562
• Pediatric Blood & Cancer • 2016 • Constitutional Mismatch Repair Deficiency in Israel: High Proportion of Founder Mutations in MMR Genes and Consanguinity. PMID:26544533
• Klinische Padiatrie • 2014 • Constitutional mismatch repair-deficiency and whole-exome sequencing as the means of the rapid detection of the causative MSH6 defect. PMID:25431869
• Cancer Research • 2001 • The distinct spectra of tumor-associated Apc mutations in mismatch repair-deficient Apc1638N mice define the roles of MSH3 and MSH6 in DNA repair and intestinal tumorigenesis. PMID:11691815
• Biochemistry • 2008 • Human mismatch repair protein MSH6 contains a PWWP domain that targets double stranded DNA. PMID:18484749

Evidence Based Scoring (AI generated)