ClinVar

Description

Variant summary: The SMAD4 c.852A>G (p.Gln284Gln) variant causes a synonymous change involving a conserved nucleotide with 4/5 splice prediction tools predicting an impact on splicing and ESE finder predicts that this variant may affect ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/121408 (1/24283), predominantly in the European (Non-Finnish) cohort, 5/66740 (1/13347), which does exceed the estimated maximal expected allele frequency for a pathogenic SMAD4 variant of 1/500000. Therefore, suggesting the variant could be a common polymorphism found in population(s) of European (Non-Finnish) origin, however, this observation needs to be cautiously considered due to presence of a pseudogene possibly being captured. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. However, clinical diagnostic laboratories have cited the variant with conflicting classifications "likely benign" or "uncertain significance." Therefore, the variant of interest has been classified as "Likely Benign," until additional information becomes available (ie, clinical and/or functional studies).