ClinVar Genomic variation as it relates to human health

Variant summary: STK11 c.1040C>T (p.Ala347Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 243968 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1040C>T has been reported in the literature in an individual affected with breast cancer (Dorling_2021) but it was also reported in unaffected controls (Momozawa_2018, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed among any breast cancer cases, but was observed among unaffected controls (Momozawa et al., 2018); Identified as a de novo variant in a patient with autism spectrum disorder evaluated by whole exome sequencing (Koire et al., 2021); This variant is associated with the following publications: (PMID: 25363768, 28900777, 30287823, 26319365, 27311873, 34011629)

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 347 of the STK11 protein (p.Ala347Val). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 578037). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This missense variant replaces alanine with valine at codon 347 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer in the literature, but has also been observed in control individuals (PMID: 26976419, 30287823, 32980694, 33471991). This variant has been identified in 4/243968 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This missense variant replaces alanine with valine at codon 347 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer in the literature, but has also been observed in control individuals (PMID: 26976419, 30287823, 32980694, 33471991). This variant has been identified in 4/243968 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.A347V variant (also known as c.1040C>T), located in coding exon 8 of the STK11 gene, results from a C to T substitution at nucleotide position 1040. The alanine at codon 347 is replaced by valine, an amino acid with similar properties. This variant has been observed in both breast cancer and healthy control groups (Momozawa Y et al. Nat Commun, 2018 Oct;9:4083; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The STK11 p.Ala347Val variant was not identified in the literature nor was it identified in the MutDB, LOVD 3.0, Zhejiang University Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs587782058) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx and Invitae), and in Cosmic (1x in skin tissue), database. The variant was identified in control databases in 4 of 241680 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33376 chromosomes (freq: 0.00003), European in 3 of 109618 chromosomes (freq: 0.00003), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala347 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. This variant is classified as a variant of uncertain significance.