ClinVar Miner

Submissions for variant NM_000455.5(STK11):c.970C>G (p.Pro324Ala)

gnomAD frequency: 0.00005  dbSNP: rs549474196
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213028 SCV000149515 likely benign not specified 2017-10-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115606 SCV000183870 likely benign Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000168083 SCV000218737 benign Peutz-Jeghers syndrome 2021-12-18 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000168083 SCV000257695 uncertain significance Peutz-Jeghers syndrome 2015-07-21 criteria provided, single submitter clinical testing
Counsyl RCV000168083 SCV000487903 uncertain significance Peutz-Jeghers syndrome 2015-12-04 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213028 SCV000602247 likely benign not specified 2021-02-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000213028 SCV000696735 benign not specified 2021-08-06 criteria provided, single submitter clinical testing Variant summary: STK11 c.970C>G (p.Pro324Ala) 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 0.00036 in 150920 control chromosomes, predominantly at a frequency of 0.0033 within the Latino subpopulation in the gnomAD database (v3.1 dataset). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 500-fold higher than 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 a benign polymorphism found primarily in populations of Latino origin. c.970C>G has been reported in the literature in individuals undergoing clinical genetic testing for hereditary cancer risk assessment (Selkirk_2014, Yurgelun_2015). 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. Eight other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=3), likely benign (n=4) / benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000168083 SCV000891006 uncertain significance Peutz-Jeghers syndrome 2022-07-12 criteria provided, single submitter clinical testing The STK11 c.970C>G (p.Pro324Ala) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 ( This variant has been reported in individuals undergoing testing for hereditary cancer predisposition (PMID: 25117502, 25980754). In addition, one individual with this variant is reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Peutz-Jeghers syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000115606 SCV000902726 likely benign Hereditary cancer-predisposing syndrome 2016-03-23 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000168083 SCV002057326 likely benign Peutz-Jeghers syndrome 2021-07-15 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000213028 SCV002065840 uncertain significance not specified 2020-03-23 criteria provided, single submitter clinical testing DNA sequence analysis of the STK11 gene demonstrated a sequence change, c.970C>G, in exon 8 that results in an amino acid change, p.Pro324Ala. This sequence change does not appear to have been previously described in patients with STK11-related disorders and has been described in the gnomAD database with a low population frequency of 0.0048% (dbSNP rs549474196). The p.Pro324Ala change affects a highly conserved amino acid residue located in a domain of the STK11 protein that is not known to be functional. The p.Pro324Ala substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro324Ala change remains unknown at this time.
Sema4,Sema4 RCV000115606 SCV002526967 likely benign Hereditary cancer-predisposing syndrome 2021-03-22 criteria provided, single submitter curation
Mayo Clinic Laboratories,Mayo Clinic RCV000213028 SCV000692054 uncertain significance not specified no assertion criteria provided clinical testing

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