ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.735C>G (p.Leu245=) (rs773147894)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464853 SCV000541161 likely benign Peutz-Jeghers syndrome 2020-11-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000569002 SCV000664346 likely benign Hereditary cancer-predisposing syndrome 2015-12-22 criteria provided, single submitter clinical testing Synonymous alterations with insufficient evidence to classify as benign
Color Health, Inc RCV000569002 SCV000691543 likely benign Hereditary cancer-predisposing syndrome 2016-08-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001199901 SCV001370657 benign not specified 2020-05-07 criteria provided, single submitter clinical testing Variant summary: STK11 c.735C>G (p.Leu245Leu) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.1e-05 in 247732 control chromosomes, predominantly at a frequency of 0.00078 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 125- fold 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 East Asian origin. To our knowledge, no occurrence of c.735C>G in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284360 SCV001470107 likely benign not provided 2019-12-06 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000464853 SCV001551058 uncertain significance Peutz-Jeghers syndrome no assertion criteria provided clinical testing The STK11 p.Leu245= variant was not identified in the literature nor was it identified in the Cosmic, LOVD 3.0, Zhejiang University, or Insight Hereditary Tumors database. The variant was identified in the following databases: dbSNP (ID: rs773147894) as "With Uncertain significance allele" and ClinVar (classified as likely benign by Invitae, Ambry Genetics, and Color Genomics). The variant was identified in control databases in 15 of 276326 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 14 of 18858 chromosomes (freq: 0.0007) and Other in 1 of 6434 chromosomes (freq: 0.0002); it was not observed in the African, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Leu245 variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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