ClinVar Genomic variation as it relates to human health

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.

The p.Arg42Leu variant in STK11 has not been previously reported in the literatu re in individuals with Peutz-Jeghers syndrome, but has been reported in ClinVar (Variation ID 403781). This variant has also has been identified in 6/8552 of Ea st Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs148830698). Computational prediction tools and conservat ion analysis do not provide strong support for or against an impact to the prote in. In summary, the clinical significance of the p.Arg42Leu variant is uncertain .

This missense variant replaces arginine with leucine at codon 42 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with lung cancer (PMID: 17711506). This variant has been identified in 15/248194 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30833958, 30287823, 24793789, 17711506)

This missense variant replaces arginine with leucine at codon 42 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with lung cancer (PMID: 17711506). This variant has been identified in 15/248194 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This alteration is classified as 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.

The STK11 p.Arg42Leu variant was identified in a lung cancer and its corresponding normal tissue in a study looking at LKB1 mutations in a cohort of Japanese lung cancer patients (Onozato 2007). The variant was also identified in dbSNP (ID: rs148830698) as “With Uncertain significance allele”, in ClinVar (classified uncertain significance by Invitae, GeneDx, Ambry Genetics, Color Genomics and Laboratory for Molecular Medicine), Clinvitae (3x), Zhejiang University Database (12X), and was not identified in Cosmic, MutDB, LOVD 3.0, or Insight Hereditary Tumors Database. The variant was identified in control databases in 14 of 245526 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017); it was observed in the East Asian population in 14 of 17234 chromosomes (freq: 0.0008), but not in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Arg42 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Leu to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.