Submissions for variant NM_000455.5(STK11):c.976C>A (p.Pro326Thr)

gnomAD frequency: 0.00001  dbSNP: rs771632414

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163989	SCV000214589	likely benign	Hereditary cancer-predisposing syndrome	2023-03-16	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.
GeneDx	RCV000766875	SCV000279185	uncertain significance	not provided	2023-07-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with early-onset breast cancer undergoing multi-gene hereditary cancer panel testing (Maxwell et al., 2016); This variant is associated with the following publications: (PMID: 25503501, 28900777)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766875	SCV000602248	uncertain significance	not provided	2024-08-12	criteria provided, single submitter	clinical testing	The STK11 c.976C>A (p.Pro326Thr) variant has been reported in the published literature as being likely benign in an individual with early-onset breast cancer (PMID: 25503501 (2015)). The frequency of this variant in the general population, 0.0000045 (1/222822 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553557	SCV000629164	likely benign	Peutz-Jeghers syndrome	2024-09-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000553557	SCV000786018	uncertain significance	Peutz-Jeghers syndrome	2018-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163989	SCV000910056	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 326 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 been reported in an individual affected with early-onset breast cancer in the literature (PMID 25503501). This variant has not been identified 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.
Genome-Nilou Lab	RCV000553557	SCV002057888	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000553557	SCV004017935	likely benign	Peutz-Jeghers syndrome	2023-04-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
Baylor Genetics	RCV003467283	SCV004205561	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 1	2023-09-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000553557	SCV004818950	uncertain significance	Peutz-Jeghers syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 326 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 been reported in an individual affected with early-onset breast cancer in the literature (PMID 25503501). This variant has not been identified 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358183	SCV001553854	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The STK11 p.Pro326Thr variant was identified in 1 of 556 proband chromosomes (frequency: 0.002) from individuals or families with early onset breast cancer (Maxwell 2015). The variant was also identified in dbSNP (ID: rs771632414) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, and two other submitters). The variant was not identified in the LOVD 3.0 database. The variant was identified in control databases in 1 of 219930 chromosomes at a frequency of 0.000005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 98674 chromosomes (freq: 0.00001), but was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Pro326 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.