Submissions for variant NM_000455.5(STK11):c.463G>T (p.Gly155Trp)

gnomAD frequency: 0.00002  dbSNP: rs763353991

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000632834	SCV000754030	uncertain significance	Peutz-Jeghers syndrome	2023-01-08	criteria provided, single submitter	clinical testing	The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 527835). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29470806). This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 155 of the STK11 protein (p.Gly155Trp).
Color Diagnostics, LLC DBA Color Health	RCV000775651	SCV000910038	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-27	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with tryptophan at codon 155 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been in two individual from a cohort affected with breast and/or ovarian cancer (PMID: 29470806). This variant has been identified in 3/196374 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.
Ambry Genetics	RCV000775651	SCV001184609	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-08	criteria provided, single submitter	clinical testing	The p.G155W variant (also known as c.463G>T), located in coding exon 3 of the STK11 gene, results from a G to T substitution at nucleotide position 463. The glycine at codon 155 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000632834	SCV002057798	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000632834	SCV002500999	uncertain significance	Peutz-Jeghers syndrome	2022-03-15	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 3 of the STK11 gene that results in the amino acid substitution of Tryptophan for Glycine at codon 155 was detected. The variant has previously been reported in breast and/or ovarian cancer patients [PMID: 29470806]. It lies in the protein kinase domain of the STK11_HUMAN protein. The observed variant c.155G>T (p.Gly155Trp) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.
Sema4, Sema4	RCV000775651	SCV002531699	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-02	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000632834	SCV004816364	uncertain significance	Peutz-Jeghers syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with tryptophan at codon 155 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/196374 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.