Submissions for variant NM_001042492.3(NF1):c.7595C>T (p.Ala2532Val)

gnomAD frequency: 0.00066  dbSNP: rs148154172

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130730	SCV000185621	likely benign	Hereditary cancer-predisposing syndrome	2015-12-03	criteria provided, single submitter	clinical testing	Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification
Invitae	RCV000989823	SCV000253228	benign	Neurofibromatosis, type 1	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000034590	SCV000570150	benign	not provided	2018-02-05	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.
PreventionGenetics, part of Exact Sciences	RCV000480111	SCV000806319	benign	not specified	2015-09-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000480111	SCV000917888	benign	not specified	2023-01-30	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.7532C>T (p.Ala2511Val) results in a non-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 0.00079 in 251060 control chromosomes. The observed variant frequency is approximately 317-fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Noonan Syndrome And Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. c.7532C>T has been reported in the literature in individuals affected Neurofibromatosis Type I (e.g. Tsipi_2018, Ben Aim_2019). These report(s) do not provide unequivocal conclusions about association of the variant with NF1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fifteen ClinVar submitters (evaluation after 2014) cites the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000480111	SCV000967009	benign	not specified	2018-04-06	criteria provided, single submitter	clinical testing	p.Ala2532Val in exon 51 of NF1: This variant is classified as benign because it has been identified in 0.93% (94/10136) of Ashkenazi Jewish chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs14 8154172). ACMG/AMP Criteria applied (Richards 2015): BA1.
Mendelics	RCV000989823	SCV001140397	likely benign	Neurofibromatosis, type 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001122667	SCV001281412	benign	Neurofibromatosis-Noonan syndrome	2017-04-28	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	RCV000989823	SCV001281413	likely benign	Neurofibromatosis, type 1	2017-04-28	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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001122668	SCV001281414	likely benign	Café-au-lait macules with pulmonary stenosis	2017-04-28	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001122669	SCV001281415	likely benign	Neurofibromatosis, familial spinal	2017-04-28	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000480111	SCV002068160	benign	not specified	2019-11-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130730	SCV002528114	benign	Hereditary cancer-predisposing syndrome	2020-07-21	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000989823	SCV002561307	benign	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000989823	SCV002567771	benign	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390138	SCV002670768	benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-04-22	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480111	SCV002774042	benign	not specified	2021-04-21	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130730	SCV002819210	likely benign	Hereditary cancer-predisposing syndrome	2022-10-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034590	SCV004142572	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	NF1: PP3, BS1
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034590	SCV000043394	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.