19-1219412-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_000455.5(STK11):c.463G>T(p.Gly155Trp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,429,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000455.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
STK11 | NM_000455.5 | c.463G>T | p.Gly155Trp | missense_variant, splice_region_variant | 3/10 | ENST00000326873.12 | NP_000446.1 | |
STK11 | NM_001407255.1 | c.463G>T | p.Gly155Trp | missense_variant, splice_region_variant | 3/9 | NP_001394184.1 | ||
STK11 | NR_176325.1 | n.1730G>T | splice_region_variant, non_coding_transcript_exon_variant | 4/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STK11 | ENST00000326873.12 | c.463G>T | p.Gly155Trp | missense_variant, splice_region_variant | 3/10 | 1 | NM_000455.5 | ENSP00000324856.6 | ||
STK11 | ENST00000652231.1 | c.463G>T | p.Gly155Trp | missense_variant, splice_region_variant | 3/9 | ENSP00000498804.1 | ||||
STK11 | ENST00000585748.3 | c.91G>T | p.Gly31Trp | missense_variant, splice_region_variant | 5/12 | 3 | ENSP00000477641.2 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 exomes AF: 0.0000153 AC: 3AN: 196374Hom.: 0 AF XY: 0.0000189 AC XY: 2AN XY: 105892
GnomAD4 exome AF: 0.00000280 AC: 4AN: 1429942Hom.: 0 Cov.: 52 AF XY: 0.00000282 AC XY: 2AN XY: 708332
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Peutz-Jeghers syndrome Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2023 | 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). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Mar 15, 2022 | 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. - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 02, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 27, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at