ClinVar

Description

Variant summary: The STK11 c.1041G>A (p.Ala347Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts no significant changes in ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. Although the variant has been identified in at least one individual with hamartomatous polyps and was suggested to result in abnormal splicing (Wei 2003, Amos 2004), these studies provided no functional evidence to that effect and this report predated the development of large scale control population databases. The variant was found in the large control database ExAC in 17 of 95258 control chromosomes from all ethnicities, but was predominantly observed in the South Asian subpopulation at a frequency of 0.001139 (15/13164). This frequency is about 73 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000156), strongly suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. Multiple clinical diagnostic laboratories have classified this variant with conflicting interpretations, including uncertain significance (1x in ClinVar), likely benign (1x in ClinVar), and benign (1x in ClinVar). Taken together, this variant is classified as benign.