Submissions for variant NM_001042492.3(NF1):c.8395G>A (p.Val2799Ile)

gnomAD frequency: 0.00006  dbSNP: rs377393842

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163718	SCV000214292	uncertain significance	Hereditary cancer-predisposing syndrome	2015-09-24	criteria provided, single submitter	clinical testing	The p.V2799I variant (also known as c.8395G>A), located in coding exon 58 of the NF1 gene, results from a G to A substitution at nucleotide position 8395. The valine at codon 2799 is replaced by isoleucine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs377393842. 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. This variant was not reported in the 1000 Genomes Project population-based cohort. To date, this alteration has been detected with an allele frequency of approximately 0.012% (greater than 110000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging andtolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233106	SCV000284528	likely benign	Neurofibromatosis, type 1	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000480546	SCV000568997	likely benign	not provided	2019-06-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31766501)
Mendelics	RCV000233106	SCV000839166	benign	Neurofibromatosis, type 1	2023-08-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818370	SCV002065405	likely benign	not specified	2021-06-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163718	SCV002528147	likely benign	Hereditary cancer-predisposing syndrome	2021-06-09	criteria provided, single submitter	curation
Ambry Genetics	RCV002408724	SCV002675328	benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-07-15	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818370	SCV004122669	likely benign	not specified	2023-10-10	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.8332G>A (p.Val2778Ile) results in a 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 9.2e-05 in 251310 control chromosomes, specifically at a frequency of 0.0011 in 10076 Ashkenazi Jewish chromosomes. This frequency is significantly higher than estimated for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (0.001 vs 0.00021), suggesting the variant is a benign polymorphism. c.8332G>A has been reported in the literature in individuals affected with Neurofibromatosis Type 1 and breast cancer, without strong evidence for causality (Melloni_2019, Guindalini_2022). These reports do 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. The following publications have been ascertained in the context of this evaluation (PMID: 35264596, 31766501). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six submitters classified the variant as benign/likely benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as likey benign.