ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1211C>T (p.Ser404Phe) (rs200078204)

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Total submissions: 13
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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 2017-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Subpopulation frequency in support of benign classification
Invitae RCV000589835 SCV000253246 likely benign not provided 2019-03-05 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 likely benign Peutz-Jeghers syndrome 2016-06-14 criteria provided, single submitter clinical testing
Color 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 likely benign not specified 2017-05-09 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
Integrated Genetics/Laboratory Corporation of America 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 RCV000589835 SCV000884614 likely benign not provided 2017-06-20 criteria provided, single submitter clinical testing The STK11 c.1211C>T;p.Ser404Phe variant has been published in the medical literature in an individual with breast cancer who also carried a pathogenic BRCA1 variant (Jalkh 2017). The variant is listed in the ClinVar database as likely benign by 5 clinical laboratories (Variation ID: 127700). The variant is listed in the dbSNP variant database (rs200078204) with an allele frequency of 0.0416 percent (5/12027 alleles) in the Exome Variant Server and up to 0.08096 percent (89/109936) in Europeans in the Genome Aggregation Database. The amino acid at this position is moderately conserved across species and computational algorithms (AlignGVGD, SIFT, PolyPhen2) predict this variant is tolerated. Considering available information, this variant is classified as likely benign. References: Jalkh N et al. Next-generation sequencing in familial breast cancer patients from Lebanon. BMC Med Genomics. 2017 Feb 15;10(1):8.

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