Submissions for variant NM_000455.5(STK11):c.566C>T (p.Thr189Ile)

gnomAD frequency: 0.00003  dbSNP: rs587781515

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129498	SCV000184270	likely benign	Hereditary cancer-predisposing syndrome	2021-05-13	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204187	SCV000260775	uncertain significance	Peutz-Jeghers syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 189 of the STK11 protein (p.Thr189Ile). This variant is present in population databases (rs587781515, gnomAD 0.01%). This missense change has been observed in individual(s) with Peutz-Jegher syndrome and breast cancer (PMID: 24307375, 30287823, 30982232). ClinVar contains an entry for this variant (Variation ID: 141128). 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 80%. 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	RCV000587196	SCV000279179	uncertain significance	not provided	2021-03-04	criteria provided, single submitter	clinical testing	Observed in individuals with reported Peutz-Jeghers syndrome and in individuals with breast cancer, but also present in unaffected control individuals (Watson 2014, Momozawa 2018, Wang 2019); Another variant at the same position, STK11 Thr189Ala, was shown to have reduced phosphorylation ability and increased ability to induce apoptosis over wild type in HT1080 cells (Karuman 2001); 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: 25005758, 23724922, 24307375, 11430832, 28706299, 30287823, 30982232, 32566746)
Counsyl	RCV000204187	SCV000489090	uncertain significance	Peutz-Jeghers syndrome	2016-08-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129498	SCV000537614	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 189 of the STK11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Peutz-Jegher syndrome (PMID: 24307375), and has been observed in both individuals with breast cancer (PMID: 30287823, 30982232), and unaffected controls (PMID: 30287823). This variant has been identified in 8/267242 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	RCV000220770	SCV000602230	uncertain significance	not specified	2016-10-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000220770	SCV000696723	likely benign	not specified	2023-10-24	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.566C>T (p.Thr189Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.8e-05 in 283350 control chromosomes. The observed variant frequency is approximately 12-fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. c.566C>T has been reported in the literature in individuals affected with breast cancer or pancreatic cancer (example, Momozawa_2018, Wang_2019, Yin_2022), without strong evidence for causality. This variant has also been present in control cohorts of two case-control studies of Biliary tract cancer and Breast cancer, respectively (Okawa_2023, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30287823, 36243179, 30982232, 24307375, 35171259, 33471991). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=11; Likely benign, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Fulgent Genetics, Fulgent Genetics	RCV000765431	SCV000896715	uncertain significance	Carcinoma of pancreas; Peutz-Jeghers syndrome; Malignant tumor of testis	2018-10-31	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030732	SCV001193748	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Baylor Genetics	RCV000204187	SCV001530398	uncertain significance	Peutz-Jeghers syndrome	2018-02-14	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000204187	SCV002057808	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000204187	SCV004018022	uncertain significance	Peutz-Jeghers syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Gharavi Laboratory, Columbia University	RCV000587196	SCV000920676	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research