ClinVar

Description

The STK11 c.464+5G>A variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, Zhejiang University Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs587781681) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae and Color Genomics Inc.), Clinvitae (3x), and in control databases in 5 of 213708 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population includes European Non-Finnish in 5 of 93184 chromosomes (freq: 0.00005) while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant was identified in a case along with a co-occurring pathogenic variant in BRCA2 (c.9097dupA, p.Thr3033AsnfsX11). The c.464+5G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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.