ClinVar Genomic variation as it relates to human health

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30287823, 28135145, 29106415)

Variant summary: STK11 c.992G>A (p.Arg331Gln) results in a conservative amino acid change in 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 4.8e-05 in 231544 control chromosomes. The observed variant frequency is approximately 8 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. c.992G>A has been reported in the literature in individuals affected with colorectal cancer (Yurgelun_2017) and breast and/or ovarian cancer (Krivokuca_2022, and Momozawa_2018); however, authors classified the variant as VUS. These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.1852_1854del, p.K618del), providing supporting evidence for a benign role (Yurgelun_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=7) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.

The STK11 c.992G>A (p.Arg331Gln) missense change has a maximum subpopulation frequency of 0.0075% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with breast cancer (PMID: 30287823). In addition, four individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Peutz-Jeghers syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as 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.

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.