rs375431906
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2
The NM_000455.5(STK11):c.1036G>A(p.Gly346Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000683 in 1,611,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000069 ( 0 hom. )
Consequence
STK11
NM_000455.5 missense
NM_000455.5 missense
Scores
2
17
Clinical Significance
Conservation
PhyloP100: 6.51
Genes affected
STK11 (HGNC:11389): (serine/threonine kinase 11) The protein encoded by this gene is a serine/threonine kinase that regulates cell polarity and energy metabolism and functions as a tumor suppressor. Mutations in this gene have been associated with the autosomal dominant Peutz-Jeghers syndrome, as well as with skin, pancreatic, and testicular cancers. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.408627).
BP6
Variant 19-1223100-G-A is Benign according to our data. Variant chr19-1223100-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141886.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.
BS2
High AC in GnomAdExome4 at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
STK11 | NM_000455.5 | c.1036G>A | p.Gly346Ser | missense_variant | Exon 8 of 10 | ENST00000326873.12 | NP_000446.1 | |
STK11 | NM_001407255.1 | c.1036G>A | p.Gly346Ser | missense_variant | Exon 8 of 9 | NP_001394184.1 | ||
STK11 | NR_176325.1 | n.2303G>A | non_coding_transcript_exon_variant | Exon 9 of 11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STK11 | ENST00000326873.12 | c.1036G>A | p.Gly346Ser | missense_variant | Exon 8 of 10 | 1 | NM_000455.5 | ENSP00000324856.6 | ||
STK11 | ENST00000652231.1 | c.1036G>A | p.Gly346Ser | missense_variant | Exon 8 of 9 | ENSP00000498804.1 | ||||
STK11 | ENST00000585748.3 | c.664G>A | p.Gly222Ser | missense_variant | Exon 10 of 12 | 3 | ENSP00000477641.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000123 AC: 3AN: 243724Hom.: 0 AF XY: 0.0000151 AC XY: 2AN XY: 132830
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GnomAD4 exome AF: 0.00000685 AC: 10AN: 1458890Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5AN XY: 725538
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Peutz-Jeghers syndrome Uncertain:3Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 16, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 14, 2024 | This missense variant replaces glycine with serine at codon 346 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 2 cases and 4 controls in a large breast cancer association study (PMID: 33471991, https://databases.lovd.nl/). This variant has been identified in 3/243724 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 | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 27, 2023 | The STK11 c.1036G>A (p.Gly346Ser) missense change has a maximum subpopulation frequency of 0.014% 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 was reported in 2 of 60,466 individuals with breast cancer and in 4 of 53,461 controls (PMID: 33471991). This variant is absent 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
not specified Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2017 | This variant is denoted STK11 c.1036G>A at the cDNA level, p.Gly346Ser (G346S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Gly346Ser was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Gly346Ser occurs at a position that is conserved across species and is located in the c-terminal domain (Hearle 2006). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether STK11 Gly346Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2021 | Variant summary: STK11 c.1036G>A (p.Gly346Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 243724 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.1036G>A has not been reported in the literature in individuals affected with Peutz-Jeghers Syndrome. However, a recent large-scale breast cancer (BrC) study reported the variant in 2/60466 BrC cases and 4/53461 healthy controls (see Dorling_2021, through LOVD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 18, 2023 | This missense variant replaces glycine with serine at codon 346 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. In a large breast cancer case-control study, this variant has been reported in 2/60466 cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 3/243724 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 21, 2023 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;M
PrimateAI
Benign
T
PROVEAN
Benign
.;N
REVEL
Benign
Sift
Benign
.;T
Sift4G
Benign
T;T
Polyphen
0.93
.;P
Vest4
MVP
MPC
0.076
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at