ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.268G>T (p.Ala90Ser) (rs141140415)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227232 SCV000291441 likely benign Multiple fibrofolliculomas 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000121101 SCV000321651 uncertain significance not specified 2017-10-05 criteria provided, single submitter clinical testing The FLCN c.268G>T variant has been identified in an individual with fibrofolliculomas, spontaneous pneumothorax, and lung cysts, but it co-occurred with another FLCN variant (Rossing 2016). FLCN Ala90Ser was also observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012) and was seen at an allele frequency of 0.06% (43/66704) in individuals of European ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Alanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. FLCN Ala90Ser occurs at a position where amino acids with properties similar to Alanine are tolerated across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether FLCN Ala90Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000332283 SCV000401023 uncertain significance Pneumothorax, primary spontaneous 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000227232 SCV000401024 benign Multiple fibrofolliculomas 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.
Ambry Genetics RCV000571977 SCV000673406 likely benign Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034791 SCV000043271 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
ITMI RCV000121101 SCV000085269 not provided not specified 2013-09-19 no assertion provided reference population

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