ClinVar Genomic variation as it relates to human health

Variant summary: STK11 c.598-7G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.1e-05 in 196798 control chromosomes. The observed variant frequency is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.598-7G>A in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 215740). Based on the evidence outlined above, the variant was classified as benign.

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA 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 classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

The STK11 c.598-7G>A variant was not identified in the literature nor was it identified in MutDB, Zhejiang University Database or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs377502057) “With Likely benign allele”, ClinVar (classified as likely benign by Invitae, Counsyl, Quest Diagnostics Nichols Institute San Juan Capistrano, and Color Genomics Inc.), Cosmic (1x in a carcinoma of the prostate), and LOVD 3.0 (1x). The variant was also identified in control databases in 17 of 223852 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017); the variant was observed in the following populations: European Non-Finnish in 14 of 97910 chromosomes (freq: 0.0001), Latino in 1 of 29348 chromosomes (freq: 0.00003), and South Asian in 2 of 26370 chromosomes (freq: 0.00008), while not observed in the African, Other, Ashkenazi Jewish, East Asian or Finnish populations. The c.598-7G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. Although positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.