ClinVar Miner

Submissions for variant NM_000455.5(STK11):c.1211C>T (p.Ser404Phe) (rs200078204)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213035 SCV000149505 likely benign not specified 2018-01-08 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 RCV000115596 SCV000186069 likely benign Hereditary cancer-predisposing syndrome 2018-12-07 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV000200450 SCV000253246 benign Peutz-Jeghers syndrome 2020-12-07 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000589835 SCV000336816 uncertain significance not provided 2015-10-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000200450 SCV000410748 benign Peutz-Jeghers syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Color Health, Inc RCV000115596 SCV000537416 likely benign Hereditary cancer-predisposing syndrome 2015-11-10 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000213035 SCV000540468 uncertain significance not specified 2016-12-02 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in ExAC with a MaxMAF of 0.160% (49 European alleles) and 0.08% in gnomAD (90 European alleles - too high for disease prevalence - highest estimates are 1/60,000). It is classified in ClinVar with 2 stars as Likely benign by 3 submitters (Invitae, Ambry, GeneDx). It has been reported in HGMD in 1 patient with Peutz-Jeghers syndrome and one with renal cell carcinoma. The amino acid is not conserved but no species have a Phe at this position.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213035 SCV000602211 benign not specified 2019-10-04 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000115596 SCV000679745 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589835 SCV000696707 benign not provided 2017-07-06 criteria provided, single submitter clinical testing Variant summary: The variant of interest, c.1211C>T (p.Ser404Phe) alters a conserved nucleotide with 2/4 in silico programs (SNPs&GO not captured here due to low reliability index), although these predictions have yet to be functionally assessed. The variant of interest was observed in a large, broad control datasets of ExAC and gnomAD with an allele frequency of 0.0009281 and 0.0004314 (52/56030 and 106/245718 chrs tested, respectively). These frequencies are significantly greater than the maximum expected allele frequency for a pathogenic STK11 variant of 0.0000063, therefore suggesting the variant of interest is benign. The variant of interest has been reported in multiple affected individuals with varying phenotypic information, including in probands from two unrelated families, where a known pathogenic variants were proven to be causative and segregated with desiase in affected family members (Yurgelun, 2017; Jalth, 2017). In aaddition, multiple clinical labs have classified this variant as "likely benign". Taking together, the variant of interest has been classified as Benign.
Counsyl RCV000200450 SCV000786088 uncertain significance Peutz-Jeghers syndrome 2018-02-20 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000589835 SCV000806071 uncertain significance not provided 2017-03-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283583 SCV000884614 likely benign none provided 2019-12-04 criteria provided, single submitter clinical testing
Mendelics RCV000200450 SCV001140949 likely benign Peutz-Jeghers syndrome 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589835 SCV001151583 uncertain significance not provided 2021-06-01 criteria provided, single submitter clinical testing
Center of Medical Genetics and Primary Health Care RCV001269488 SCV001449141 benign Malignant tumor of breast no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000589835 SCV001549584 likely benign not provided no assertion criteria provided clinical testing The STK11 p.Ser404Phe variant was identified in 7 of 3890 proband chromosomes (frequency: 0.002) from Lebanese, German, and American individuals or families with breast cancer, hereditary breast cancer, CRC, or Lynch syndrome (Jalkh 2017, Tung 2016, Kraus 2014, Yurgelun 2015). In 1 proband with 3 family members diagnosed with breast cancer, exome sequencing identified the variant co-occurring with 2 other disease-causing mutations (BRCA1 c.G131T, p.C44F and SLX4 c.G421T, p.G141W) (Jalkh 2017). The variant was also identified in dbSNP (ID: rs200078204) “With other allele”, ClinVar (6x as likely benign by GeneDx, Ambry Genetics, Invitae, Illumina, Color Genomics and Quest Diagnostics Nichols Institute San Juan Capistrano and 2x as uncertain significance by EGL Genetic Diagnostics and Laboratory for Molecular Medicine), and LOVD 3.0 (2x). The variant was not identified in Cosmic, MutDB,Zhejiang Colon Cancer Database, and Insight Hereditary Tumors Database. The variant was identified in control databases in 106 of 245718 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was seen in the following populations: African in 4 of 20584 chromosomes (freq: 0.0002), Other in 3 of 5868 chromosomes (freq: 0.0005), Latino in 7 of 32154 chromosomes (freq: 0.0002), European Non-Finnish in 89 of 109936 chromosomes (freq: 0.0008), and South Asian in 3 of 27996 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian or Finnish populations. The p.Ser404Phe residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics,Academic Medical Center RCV000589835 SCV001920164 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000213035 SCV001957129 benign not specified no assertion criteria provided clinical testing

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