Variant Synonymizer: Platform to identify mutations defined in different ways is available now!

VarSy

Over 2,000 gene–disease validation summaries are now available—no login required!

Browse Summaries

MAP3K6 – Hereditary Diffuse Gastric Adenocarcinoma

Initial evidence for MAP3K6 as a predisposition gene for hereditary diffuse gastric adenocarcinoma (HDGC) arose from a PLoS Genetics study identifying a germline MAP3K6 variant, p.Pro946Leu, in a large Maritime Canada family with CDH1‐negative familial gastric cancer, accompanied by a somatic second‐hit, c.1516C>T (p.His506Tyr), and DNA hypermethylation in tumors (PMID:25340522). Screening of 115 additional unrelated CDH1‐negative individuals revealed four more unique MAP3K6 coding variants in six probands, supporting autosomal dominant inheritance but with limited segregation data and no recurrent founder alleles.

Subsequent targeted sequencing in 286 unexplained familial gastric cancer cases found three predicted deleterious MAP3K6 variants, but their similar frequency in population databases led authors to conclude that MAP3K6 should no longer be considered a GC predisposition gene (PMID:29330337). Taken together, genetic and functional data (murine tumor suppressor models; somatic second hits) are insufficient to confirm MAP3K6 as a penetrant HDGC gene, and its role remains disputed.

Key Take-home: MAP3K6 harbors rare variants in HDGC but lacks robust segregation, recurrence, or case‐control support, limiting its clinical utility for genetic diagnosis of hereditary diffuse gastric adenocarcinoma.

References

  • PLoS genetics • 2014 • Germline mutations in MAP3K6 are associated with familial gastric cancer. PMID:25340522
  • Journal of medical genetics • 2018 • Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility. PMID:29330337

Evidence Based Scoring (AI generated)

Gene–Disease Association

Disputed

Initial report: p.Pro946Leu in one multiplex family and five additional variants in 115 probands ([PMID:25340522]); refuted by case–control study showing similar MAP3K6 variant frequency in 286 GC cases vs population controls ([PMID:29330337]).

Genetic Evidence

Limited

Six probands with unique heterozygous variants; minimal segregation; no recurrent or founder alleles; variants also occur in general population.

Functional Evidence

Limited

Murine tumor suppressor models and somatic second‐hit/hypermethylation in tumors support a role, but direct gastric‐specific functional assays and rescue studies are lacking.