ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1994C>T (p.Ser665Phe) (rs145891889)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129662 SCV000184460 likely benign Hereditary cancer-predisposing syndrome 2015-09-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification,Subpopulation frequency in support of benign classification
Invitae RCV000587577 SCV000252676 benign not provided 2019-03-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000121628 SCV000269447 benign not specified 2015-04-07 criteria provided, single submitter clinical testing p.Ser665Phe in exon 17 of NF1: This variant is not expected to have clinical sig nificance because it has been identified in 0.8% (81/10324) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs145891889).
GeneDx RCV000587577 SCV000521058 likely benign not provided 2018-02-12 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.
Integrated Genetics/Laboratory Corporation of America RCV000121628 SCV000696388 benign not specified 2019-01-30 criteria provided, single submitter clinical testing Variant summary: NF1 c.1994C>T (p.Ser665Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 282364 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0077 in the gnomAD database, including 2 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 37-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 African origin. However, this region is affected by pseudogene interference therefore these population frequency data need to be cautiously considered. c.1994C>T has been reported in the literature in an affected individual (Fahsold 2000). This report however does not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant predominantly as likely benign/benign (7x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Center for Human Genetics, Inc RCV000200171 SCV000781933 likely benign Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000200171 SCV000803613 uncertain significance Neurofibromatosis, type 1 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Neurofibromatosis 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder.
PreventionGenetics,PreventionGenetics RCV000121628 SCV000806260 benign not specified 2016-05-11 criteria provided, single submitter clinical testing
Mendelics RCV000200171 SCV000839134 likely benign Neurofibromatosis, type 1 2018-07-02 criteria provided, single submitter clinical testing
ITMI RCV000121628 SCV000085826 not provided not specified 2013-09-19 no assertion provided reference population

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