19-1226570-C-T
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BP6BS1BS2
The NM_000455.5(STK11):c.1225C>T(p.Arg409Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,588,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000455.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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STK11 | NM_000455.5 | c.1225C>T | p.Arg409Trp | missense_variant | Exon 9 of 10 | ENST00000326873.12 | NP_000446.1 | |
STK11 | NR_176325.1 | n.2492C>T | non_coding_transcript_exon_variant | Exon 10 of 11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STK11 | ENST00000326873.12 | c.1225C>T | p.Arg409Trp | missense_variant | Exon 9 of 10 | 1 | NM_000455.5 | ENSP00000324856.6 | ||
STK11 | ENST00000585748.3 | c.853C>T | p.Arg285Trp | missense_variant | Exon 11 of 12 | 3 | ENSP00000477641.2 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152252Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000872 AC: 17AN: 194938Hom.: 0 AF XY: 0.0000934 AC XY: 10AN XY: 107116
GnomAD4 exome AF: 0.0000383 AC: 55AN: 1435836Hom.: 0 Cov.: 31 AF XY: 0.0000379 AC XY: 27AN XY: 712116
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74384
ClinVar
Submissions by phenotype
Peutz-Jeghers syndrome Uncertain:6Benign:1
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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. -
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Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 50 year old female diagnosed with colon cancer at age 49. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -
not specified Uncertain:3Benign:1
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Variant summary: STK11 c.1225C>T (p.Arg409Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 194938 control chromosomes. The observed variant frequency is approximately 14 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.1225C>T has been reported in the literature as a VUS in individuals with breast cancer (example, Couch_2015, Tung_2014, Goldescu_2018), as an uninformative genotype in a PJS proband who had normal levels of TP53 activity (Jiang_2018), and in unaffected controls in a Japanese population based CRC screening study reporting a final classification as benign (Fujita_2020). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 25452441, 25186627, 17676035, 29785153, 33309985, 30092773). ClinVar contains an entry for this variant (Variation ID: 135917). Based on the evidence outlined above, the variant was classified as likely benign. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
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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. -
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not provided Uncertain:1Benign:1
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in one individual with a clinical diagnosis of Peutz-Jeghers syndrome, without a family history of disease, as well as in individuals with breast cancer (Couch 2015, Tung 2015, Goidescu 2018, Jiang 2018); Published functional studies demonstrate no damaging effect: normal P53 activity (Jiang 2018) This variant is associated with the following publications: (PMID: 30287823, 30092773, 31422574, 31159747, 29785153, 25186627, 25925381, 17676035, 25452441) -
The STK11 c.1225C>T (p.Arg409Trp) variant has been reported in individuals affected with breast cancer (PMID: 30287823 (2018), 29785153 (2018), 25452441 (2015), 25186627 (2015)). This variant has also been identified in a reportedly healthy individual (PMID: 36243179 (2022)). This variant has been shown to have no deleterious effect on TP53 activity, however, more studies are needed to determine the global effect of this variant on STK11 protein function (PMID: 30092773 (2018)). The frequency of this variant in the general population, 0.0003 (3/10150 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Breast carcinoma Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at