Submissions for variant NM_000455.5(STK11):c.608C>T (p.Pro203Leu)

gnomAD frequency: 0.00002  dbSNP: rs587782379

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131373	SCV000186349	likely benign	Hereditary cancer-predisposing syndrome	2021-12-30	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	RCV000219794	SCV000279960	uncertain significance	not provided	2023-05-16	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; Not observed in any cases, but was observed in the unaffected controls in a breast cancer study (Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 30287823, 15863673)
Invitae	RCV000536349	SCV000629131	uncertain significance	Peutz-Jeghers syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 203 of the STK11 protein (p.Pro203Leu). This variant is present in population databases (rs587782379, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 142317). 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 with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000131373	SCV000910042	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 203 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, but has been observed in control individuals (PMID: 30287823, 32980694). This variant has been identified in 4/204582 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	RCV000219794	SCV001134846	uncertain significance	not provided	2019-02-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000536349	SCV002057813	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000536349	SCV004816380	uncertain significance	Peutz-Jeghers syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 203 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, but has been observed in control individuals (PMID: 30287823, 32980694). This variant has been identified in 4/204582 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.