Submissions for variant NM_000455.5(STK11):c.937C>T (p.His313Tyr)

gnomAD frequency: 0.00001  dbSNP: rs730881987

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000161010	SCV000211721	uncertain significance	not provided	2014-05-19	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000226358	SCV000284881	uncertain significance	Peutz-Jeghers syndrome	2023-07-28	criteria provided, single submitter	clinical testing	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).
Color Diagnostics, LLC DBA Color Health	RCV001181036	SCV001346093	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-25	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000226358	SCV002057876	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001181036	SCV002684942	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-13	criteria provided, single submitter	clinical testing	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.
All of Us Research Program, National Institutes of Health	RCV000226358	SCV004818938	uncertain significance	Peutz-Jeghers syndrome	2023-04-27	criteria provided, single submitter	clinical testing