Submissions for variant NM_000455.5(STK11):c.818C>T (p.Ala273Val)

gnomAD frequency: 0.00001  dbSNP: rs761164605

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001320760	SCV001511558	uncertain significance	Peutz-Jeghers syndrome	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 273 of the STK11 protein (p.Ala273Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs761164605, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with STK11-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
GeneDx	RCV001773639	SCV002003299	uncertain significance	not provided	2020-09-28	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV001320760	SCV002057847	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003166854	SCV003858822	likely benign	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV003462893	SCV004205548	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 1	2023-10-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001320760	SCV004829713	uncertain significance	Peutz-Jeghers syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 273 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 not been reported in individuals affected with STK11-related disorders in the literature. This variant has been identified in 2/243892 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.