Submissions for variant NM_001042492.3(NF1):c.1994C>T (p.Ser665Phe)

gnomAD frequency: 0.00220  dbSNP: rs145891889

Total submissions: 23

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	In silico models in agreement (benign);Other data supporting benign classification;Subpopulation frequency in support of benign classification
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200171	SCV000252676	benign	Neurofibromatosis, type 1	2024-02-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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	benign	not provided	2021-05-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10712197, 24803665, 15060124, 24728327, 27322474, 23771920, 28371134, 26154128, 33562071)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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, 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, part of Exact Sciences	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
Illumina Laboratory Services, Illumina	RCV001124835	SCV001283831	benign	Neurofibromatosis, familial spinal	2017-11-20	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001124836	SCV001283832	benign	Neurofibromatosis-Noonan syndrome	2017-11-20	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001124837	SCV001283833	benign	Café-au-lait macules with pulmonary stenosis	2017-11-20	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000200171	SCV001283834	benign	Neurofibromatosis, type 1	2017-11-20	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000200171	SCV001479096	likely benign	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121628	SCV002066473	likely benign	not specified	2020-02-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129662	SCV002527436	benign	Hereditary cancer-predisposing syndrome	2020-07-31	criteria provided, single submitter	curation
Medical Genetics, University of Parma	RCV000200171	SCV002567760	benign	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587577	SCV002774039	benign	not provided	2017-04-28	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129662	SCV002819225	benign	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001124835	SCV004016428	benign	Neurofibromatosis, familial spinal	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587577	SCV004184665	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	NF1: BS1, BS2
Ambry Genetics	RCV004558311	SCV005048590	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-04-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ITMI	RCV000121628	SCV000085826	not provided	not specified	2013-09-19	no assertion provided	reference population