Submissions for variant NM_001042492.3(NF1):c.1894T>A (p.Cys632Ser)

gnomAD frequency: 0.00005  dbSNP: rs370789267

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220588	SCV000274138	uncertain significance	Hereditary cancer-predisposing syndrome	2016-02-22	criteria provided, single submitter	clinical testing	The p.C632S variant (also known as c.1894T>A), located in coding exon 17 of the NF1 gene, results from a T to A substitution at nucleotide position 1894. The cysteine at codon 632 is replaced by serine, an amino acid with dissimilar properties.This alteration was previously reported in 1/681 individuals in a healthy, ancestrally diverse cohort via genome sequencing, having been detected in 1/331European individuals in this cohort (BodianDL et al.PLoSONE2014;9(4):e94554). This variant was previously reported in the SNPDatabase as rs370789267. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in0.01% (1/8600) European American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.C632S remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234708	SCV000284394	likely benign	Neurofibromatosis, type 1	2025-01-29	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000712402	SCV000842884	uncertain significance	not provided	2018-03-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121630	SCV000917881	uncertain significance	not specified	2024-08-09	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.1894T>A (p.Cys632Ser) 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 2.4e-05 in 251898 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1894T>A in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 134883). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000234708	SCV001482852	uncertain significance	Neurofibromatosis, type 1	2019-03-22	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000712402	SCV001811698	likely benign	not provided	2023-04-25	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Sema4, Sema4	RCV000220588	SCV002527426	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-10	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000234708	SCV002561958	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483222	SCV002789985	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-11-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558312	SCV005048584	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-03-24	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000712402	SCV005624528	uncertain significance	not provided	2024-10-10	criteria provided, single submitter	clinical testing	The NF1 c.1894T>A (p.Cys632Ser) variant has been reported in the published literature in individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)), in an individual with an unspecified advanced cancer (PMID: 28873162 (2017)), as well as in reportedly healthy individuals (PMID: 24728327 (2014) and 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.000047 (6/128992 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
ITMI	RCV000121630	SCV000085828	not provided	not specified	2013-09-19	no assertion provided	reference population