rs121913320
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000455.5(STK11):c.790_793del(p.Phe264ArgfsTer22) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L263L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
STK11
NM_000455.5 frameshift
NM_000455.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.73
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-1221264-GTTGT-G is Pathogenic according to our data. Variant chr19-1221264-GTTGT-G is described in ClinVar as [Pathogenic]. Clinvar id is 372523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1221264-GTTGT-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STK11 | NM_000455.5 | c.790_793del | p.Phe264ArgfsTer22 | frameshift_variant | 6/10 | ENST00000326873.12 | |
STK11 | NM_001407255.1 | c.790_793del | p.Phe264ArgfsTer22 | frameshift_variant | 6/9 | ||
STK11 | NR_176325.1 | n.2057_2060del | non_coding_transcript_exon_variant | 7/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STK11 | ENST00000326873.12 | c.790_793del | p.Phe264ArgfsTer22 | frameshift_variant | 6/10 | 1 | NM_000455.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Peutz-Jeghers syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 372523). This variant is also known as c.787del4. This premature translational stop signal has been observed in individual(s) with Peutz-Jeghers syndrome (PMID: 9809980, 15863673, 16287113, 17010210, 23718779, 26979979). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe264Argfs*22) in the STK11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 12, 2024 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 10, 2019 | Frameshift variant predicted to result in protein truncation [or nonsense mediated decay] in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12552571, 9809980, 16287113, 23718779, 17404884, 19727776, 17010210, 25742471, 11103790, 15863673) - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 06, 2017 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 09, 2023 | The c.790_793delTTTG pathogenic mutation, located in coding exon 6 of the STK11 gene, results from a deletion of 4 nucleotides at nucleotide positions 790 to 793, causing a translational frameshift with a predicted alternate stop codon (p.F264Rfs*22). This alteration has been identified in multiple cohorts of patients with a clinical diagnosis of Peutz-Jegher syndrome (Resta N et al. Cancer Res. 1998 Nov;58:4799-801; Schumacher V et al. J. Med. Genet. 2005 May;42:428-35; Thakur N et al. BMC Med. Genet. 2006 Sep;7:73; Jiang YL et al. Cancer Genet. 2019 01;230:47-57). Of note, this alteration is also designated as 787del4 in the published literature. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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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