ClinVar

Description

Variant summary: SMAD4 c.-3C>G is located in the untranslated mRNA region upstream of the initiation codon. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 245968 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-3C>G has been reported in the literature in individuals affected with Lynch Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been reported (BRCA1 c.5266dupC, p.Q1756fs*74) in our laboratory providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.