ClinVar Genomic variation as it relates to human health

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.

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This variant is denoted STK11 c.1041G>A at the DNA level. Although the variant is silent at the coding level, preserving an Alanine at codon 347, this variant has been identified in at least one individual with hamartomatous polyps and was suggested to result in abnormal splicing (Wei 2003, Amos 2004); however, splicing models at our laboratory do not predict an effect on splicing. STK11 c.1041G>A was not observed at a significant allele frequency in 1000 Genomes. The nucleotide which is altered, a guanine (G) at base 1041, is not conserved across species. Based on currently available information, it is unclear whether STK11 c.1041G>A is pathogenic or benign. We consider this to be a variant of uncertain significance.

The STK11 p.Ala347Ala variant was identified in 1 of 84 proband chromosomes (frequency: 0.01) from individuals or families with Peutz-Jaghers Syndrome (Amos 2004). The variant was identified in dbSNP (rs537906142) as “with likely benign, uncertain significance allele”, in ClinVar (interpreted as "benign" by Invitae and 2 others, "likely benign" by Ambry Genetics and "uncertain significance" by GeneDx). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 27 of 241,514 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant as this frequency is well above the known prevalence of Peutz-Jagher Syndrome (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 109,548 chromosomes (freq: 0.000009), Finnish in 1 of 21,340 chromosomes (freq: 0.00005), and South Asian in 25 of 30,278 chromosomes (freq: 0.0008). The variant was not observed in the African, Other, Latino, Ashkenazi Jewish, or East Asian populations. The p.Ala347= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicted the creation of a new splice site. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).