chr19-1223001-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000455.5(STK11):c.937C>T(p.His313Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000256 in 1,562,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H313Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000455.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STK11 | NM_000455.5 | c.937C>T | p.His313Tyr | missense_variant | 8/10 | ENST00000326873.12 | |
STK11 | NM_001407255.1 | c.937C>T | p.His313Tyr | missense_variant | 8/9 | ||
STK11 | NR_176325.1 | n.2204C>T | non_coding_transcript_exon_variant | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STK11 | ENST00000326873.12 | c.937C>T | p.His313Tyr | missense_variant | 8/10 | 1 | NM_000455.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000213 AC: 3AN: 1409832Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 695656
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
Peutz-Jeghers syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 27, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function. This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 313 of the STK11 protein (p.His313Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 182915). - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 25, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 13, 2023 | The p.H313Y variant (also known as c.937C>T), located in coding exon 8 of the STK11 gene, results from a C to T substitution at nucleotide position 937. The histidine at codon 313 is replaced by tyrosine, an amino acid with similar properties. This variant has been reported in an individual affected with colorectal cancer (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2014 | This variant is denoted STK11 c.937C>T at the cDNA level, p.His313Tyr (H313Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 His313Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 His313Tyr occurs at a position that is well conserved across species within the C-terminal of the protein but not located in a known functional domain (Hearle 2006). In addition, in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether STK11 His313Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at