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

gnomAD frequency: 0.00005  dbSNP: rs549474196

Total submissions: 15

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	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.
Invitae	RCV000168083	SCV000218737	benign	Peutz-Jeghers syndrome	2024-02-01	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	RCV003477496	SCV000602247	likely benign	not provided	2023-05-26	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 (https://gnomad.broadinstitute.org/). 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, https://whi.color.com/). 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
Myriad Genetics, Inc.	RCV000168083	SCV004017983	likely benign	Peutz-Jeghers syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003964969	SCV004777585	likely benign	STK11-related disorder	2024-02-19	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Mayo Clinic Laboratories, Mayo Clinic	RCV000213028	SCV000692054	uncertain significance	not specified		no assertion criteria provided	clinical testing