ClinVar Genomic variation as it relates to human health

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

STK11: BP4, BP7

The STK11 p.Pro275= variant was not identified in the literature nor was it identified in the following databases: Cosmic, MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs202011521) as “With other allele”, ClinVar (as benign by GeneDx, Ambry Genetics, and Invitae, as likely benign by Quest Diagnostics and Color Genomics, and as uncertain significance by Ilumina), and Clinvitae (with conflicting interpretations of pathogenicity). The variant was identified in control databases in 53 of 271464 chromosomes at a frequency of 0.000195 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 23358 chromosomes (freq: 0.000086), Other in 3 of 6346 chromosomes (freq: 0.000473), Latino in 8 of 33978 chromosomes (freq: 0.000235), European (Non-Finnish) in 13 of 123704 chromosomes (freq: 0.000105), Ashkenazi Jewish in 27 of 9978 chromosomes (freq: 0.002706); it was not observed in the East Asian, European (Finnish), and South Asian populations. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing with a possible creation of a cryptic splice site; this is not very predictive of pathogenicity. The p.Pro275= 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. 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.