Submissions for variant NM_000455.5(STK11):c.200T>C (p.Leu67Pro)

dbSNP: rs137853077

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000007871	SCV000488678	likely pathogenic	Peutz-Jeghers syndrome	2016-05-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000440305	SCV000514792	pathogenic	not provided	2023-03-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: disrupted autophosphorylation of STK11 and absent kinase activity (Mehenni et al., 1998; Nezu et al., 1999; Ylikorkala et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16707622, 9428765, 11389158, 15121768, 29447078, 15863673, 15987703, 9887330, 10441497, 9837816)
Ambry Genetics	RCV000492681	SCV000580921	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-07-01	criteria provided, single submitter	clinical testing	The p.L67P variant (also known as c.200T>C), located in coding exon 1 of the STK11 gene, results from a T to C substitution at nucleotide position 200. The leucine at codon 67 is replaced by proline, an amino acid with similar properties. This alteration was seen in multiple unrelated individuals meeting diagnostic criteria for Peutz-Jeghers syndrome (Hemminki A et al. Nature 1998 Jan;391(6663):184-7; Hearle N et al. Clin. Cancer Res. 2006 May;12(10):3209-15; Ambry internal data). This variant was previously reported in the SNPDatabase as rs137853077. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 125000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000440305	SCV001134840	likely pathogenic	not provided	2019-08-20	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/272834 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Invitae	RCV000007871	SCV001391505	likely pathogenic	Peutz-Jeghers syndrome	2020-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with proline at codon 67 of the STK11 protein (p.Leu67Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu67 amino acid residue in STK11. Other variant(s) that disrupt this residue have been observed in individuals with STK11-related conditions (PMID: 11389158), which suggests that this may be a clinically significant amino acid residue. This variant has been reported to affect STK11 protein function (PMID: 9837816, 10441497, 9887330, 15987703). This variant has been observed in individuals with clinical features of Peutz-Jeghers syndrome (PMID: 9428765, 15121768). ClinVar contains an entry for this variant (Variation ID: 7445). This variant is not present in population databases (ExAC no frequency).
Genome-Nilou Lab	RCV000007871	SCV002057355	likely pathogenic	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
OMIM	RCV000007871	SCV000028076	pathogenic	Peutz-Jeghers syndrome	1998-01-08	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000007871	SCV000510527	likely pathogenic	Peutz-Jeghers syndrome	2016-05-13	no assertion criteria provided	literature only