Submissions for variant NM_000455.5(STK11):c.94A>G (p.Thr32Ala)

gnomAD frequency: 0.00001  dbSNP: rs755210880

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229700	SCV000284882	uncertain significance	Peutz-Jeghers syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 32 of the STK11 protein (p.Thr32Ala). This variant is present in population databases (rs755210880, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer and colorectal cancer (PMID: 34326862, 34761457). ClinVar contains an entry for this variant (Variation ID: 237806). 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.
Counsyl	RCV000229700	SCV000489330	uncertain significance	Peutz-Jeghers syndrome	2016-09-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000479327	SCV000565596	uncertain significance	not provided	2023-12-11	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; Observed in individuals with breast or colorectal cancer (PMID: 33471991, 34761457); This variant is associated with the following publications: (PMID: 34761457, 34326862, 30476936, 33471991)
Ambry Genetics	RCV000561474	SCV000664333	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-18	criteria provided, single submitter	clinical testing	The p.T32A variant (also known as c.94A>G), located in coding exon 1 of the STK11 gene, results from an A to G substitution at nucleotide position 94. The threonine at codon 32 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000561474	SCV000686708	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 32 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 STK11-related disorders in the literature. This variant has been identified in 2/275700 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	RCV000479327	SCV000888651	uncertain significance	not provided	2018-03-09	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000229700	SCV002057733	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000561474	SCV002526965	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000229700	SCV004017940	uncertain significance	Peutz-Jeghers syndrome	2023-04-12	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401170	SCV004122525	uncertain significance	not specified	2023-10-05	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.94A>G (p.Thr32Ala) 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 4e-06 in 247484 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.94A>G has been reported in the literature in individuals affected with ovarian cancer or colorectal cancer (Bhai_2021, Mikaeel_2021). These reports 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: 34326862, 34761457, 30476936). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000229700	SCV004816311	uncertain significance	Peutz-Jeghers syndrome	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 32 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 STK11-related disorders in the literature. This variant has been identified in 2/275700 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.
Fulgent Genetics, Fulgent Genetics	RCV005025382	SCV005655476	uncertain significance	Peutz-Jeghers syndrome; Melanoma, cutaneous malignant, susceptibility to, 1; Familial pancreatic carcinoma; Germ cell tumor of testis	2024-06-20	criteria provided, single submitter	clinical testing
Gharavi Laboratory, Columbia University	RCV000479327	SCV000920675	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research