ClinVar Genomic variation as it relates to human health

Variant summary: STK11 c.559G>A (p.Gly187Ser) results in a non-conservative amino acid change located in the catalytic domain (IPR039154) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 284338 control chromosomes (gnomAD and publication data). The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome (PJS) phenotype (6.3e-06), strongly suggesting that the variant is benign. Though the variant, c.559G>A, has been reported in the literature in individuals affected with lung-, and breast cancer (Kim_2010, Couch_2015, Momozawa_ 2018), in one of these cases it was noted that the affected patient did not have any clinical manifestations of PJS (Kim_2010); moreover the variant was also reported in multiple healthy controls (Kim_2010, Momozawa_ 2018 and in the FLOSSIES database). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (4x) or likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.

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.559G>A at the cDNA level, p.Gly187Ser (G187S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). This variant was observed in at least one individual with triple negative breast cancer (Couch 2015). STK11 Gly187Ser was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Gly187Ser occurs at a position that is not conserved and is located in the protein kinase domain and in the region required for binding of substrate and initiation of phospho transfer (UniProt, Hearle 2006). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether STK11 Gly187Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

DNA sequence analysis of the STK11 gene demonstrated a sequence change, c.559G>A, in exon 4 that results in an amino acid change, p.Gly187Ser. This sequence has been previously described in individuals with breast cancer, small cell lung cancers (NSCLC) and has also been described in control population (PMIDs: 25452441, 30287823, 20082862 and FLOSSIES database). This sequence change has been described in the gnomAD database in eight individuals which corresponds to a population frequency of 0.003% (dbSNP rs587782032). The p.Gly187Ser change affects a poorly conserved amino acid residue located in a domain of the STK11 protein that is known to be functional. The p.Gly187Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly187Ser change remains unknown at this time.

The STK11 p.Gly187Ser variant was identified in 3 of 10699 proband chromosomes (frequency: 0.0003) from triple negative BRCA families and Japanese women with breast cancer and was present in 2 of 11241 control chromosomes (frequency: 0.00018) from healthy individuals (Couch 2015, Momozawa 20118). The variant was also identified in dbSNP (ID: rs587782032) as “With Uncertain significance allele”, ClinVar (5x as uncertain significance and 1x as likely benign by Ambry Genetics, Invitae, GeneDx, Integrated Genetics, Counsyl, Mendelics) and LOVD 3.0 (4x as uncertain significance). The variant was identified in control databases in 7 of 233812 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5256 chromosomes (freq: 0.0002), European Non-Finnish in 5 of 105720 chromosomes (freq: 0.00005) and East Asian in 1 of 16594 chromosomes (freq: 0.00006), while the variant was not observed in the African, Latino, Ashkenazi Jewish, European Finnish or South Asian populations. The p.Gly187 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.