Submissions for variant NM_000455.5(STK11):c.944C>T (p.Pro315Leu)

gnomAD frequency: 0.00002  dbSNP: rs766958608

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000457133	SCV000541157	likely benign	Peutz-Jeghers syndrome	2024-01-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000567303	SCV000664337	likely benign	Hereditary cancer-predisposing syndrome	2018-10-01	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.
Color Diagnostics, LLC DBA Color Health	RCV000567303	SCV000911164	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 315 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 hereditary cancer in the literature. This variant has been identified in 2/189020 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284363	SCV001470112	uncertain significance	not provided	2020-04-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001527035	SCV001737859	uncertain significance	not specified	2021-05-29	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.944C>T (p.Pro315Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 189020 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.944C>T in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=2; Likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001284363	SCV001751143	uncertain significance	not provided	2023-02-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 30171174, 12372054, 28900777)
Genome-Nilou Lab	RCV000457133	SCV002057323	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150213	SCV003837870	uncertain significance	Breast and/or ovarian cancer	2022-03-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000457133	SCV004818940	uncertain significance	Peutz-Jeghers syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 315 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 hereditary cancer in the literature. This variant has been identified in 2/189020 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.