ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.6929C>T (p.Pro2310Leu)

gnomAD frequency: 0.00003  dbSNP: rs148736217
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129366 SCV000184130 likely benign Hereditary cancer-predisposing syndrome 2016-01-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Other data supporting benign classification
Invitae RCV001082296 SCV000218706 benign Neurofibromatosis, type 1 2020-12-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000214790 SCV000272222 benign not specified 2017-10-10 criteria provided, single submitter clinical testing p.Pro2310Leu in exon 47 of NF1: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (52/10152) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org/; dbSNP rs148736217). ACMG/AMP Criteria applied: BA1 (Richards 2015).
GeneDx RCV000034587 SCV000720772 benign not provided 2019-09-26 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 29089047, 22703879, 28873162)
PreventionGenetics,PreventionGenetics RCV000214790 SCV000806304 likely benign not specified 2020-01-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001122580 SCV001281306 uncertain significance Café-au-lait macules with pulmonary stenosis 2018-01-15 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 Laboratory Services,Illumina RCV001122581 SCV001281307 uncertain significance Neurofibromatosis, familial spinal 2018-01-15 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 Laboratory Services,Illumina RCV001082296 SCV001281308 uncertain significance Neurofibromatosis, type 1 2018-01-15 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 Laboratory Services,Illumina RCV001122582 SCV001281309 uncertain significance Neurofibromatosis-Noonan syndrome 2018-01-15 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000214790 SCV002041524 benign not specified 2021-11-30 criteria provided, single submitter clinical testing Variant summary: NF1 c.6866C>T (p.Pro2289Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251474 control chromosomes, predominantly at a frequency of 0.0052 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 25 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.6866C>T has been reported in the literature in individuals affected with various cancers (Jones_2015, Johnston_2012, Chitalia_2019), however these reports do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1 or other cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed this variant after 2014: Four have classified this variant as likely benign/benign, and two as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen RCV000034587 SCV002063600 likely benign not provided 2021-12-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000214790 SCV002070403 likely benign not specified 2020-08-19 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000129366 SCV002530170 likely benign Hereditary cancer-predisposing syndrome 2021-02-06 criteria provided, single submitter curation
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034587 SCV000043392 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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