Submissions for variant NM_001042492.3(NF1):c.6172A>G (p.Ile2058Val)

gnomAD frequency: 0.00017  dbSNP: rs201712827

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130497	SCV000185366	likely benign	Hereditary cancer-predisposing syndrome	2015-06-28	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Other data supporting benign classification
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205125	SCV000262159	benign	Neurofibromatosis, type 1	2024-02-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121636	SCV000731960	uncertain significance	not specified	2017-09-19	criteria provided, single submitter	clinical testing	The p.Ile2058Val variant in NF1 has not been previously reported in individuals with RASopathies, but has been reported in ClinVar (Variation ID: 134887). It ha s been identified in 22/125856 European chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201712827). Computatio nal prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of t he p.Ile2058Val variant is uncertain.
Mendelics	RCV004700428	SCV001140387	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000205125	SCV001367524	uncertain significance	Neurofibromatosis, type 1	2019-02-20	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
GeneDx	RCV001588968	SCV001815315	likely benign	not provided	2019-04-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32107864, 24728327)
Genetic Services Laboratory, University of Chicago	RCV000121636	SCV002071889	uncertain significance	not specified	2020-12-24	criteria provided, single submitter	clinical testing	DNA sequence analysis of the NF1 gene demonstrated a sequence change, c.6109A>G, in exon 41 that results in an amino acid change, p.Ile2037Val. This sequence change does not appear to have been previously described in patients with NF1-related disorders and has been described in the gnomAD database with a low population frequency of 0.016% in non-Finnish European subpopulation (dbSNP rs201712827). The p.Ile2037Val change affects a moderately conserved amino acid residue located in a domain of the NF1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile2037Val substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile2037Val change remains unknown at this time.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000205125	SCV002505549	uncertain significance	Neurofibromatosis, type 1	2022-04-28	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PP2
Sema4, Sema4	RCV000130497	SCV002527643	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-08	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121636	SCV002556259	likely benign	not specified	2022-06-30	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.6109A>G (p.Ile2037Val) results in a conservative amino acid change which is located outside of any known functional domain or repeat of the encoded protein sequence (InterPro, UniProt). Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250150 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than the estimated maximum expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (0.00021), allowing no conclusion about variant significance. However, the variant is reported with a much higher occurrence in the Amish (i.e. 11/910 alleles; a frequency of 0.012), suggesting that the variant might be a benign polymorphism. The variant, c.6109A>G, has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (Koczkowska_2018) or suspected RASopathy (Witkowski_2020), however in one of these reports the variant was found in a family in the proband, and not found in two affected family members, while all affected family members had a (likely) pathogenic variant, which segregated with the disease phenotype (Koczkowska_2018). In addition, the variant was reported in patients with breast cancer (Dorling_2021), but was also found in healthy controls (Bodian_2014, Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=8) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV001588968	SCV004699779	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	NF1: PP2, BS1
Ambry Genetics	RCV004558314	SCV005047962	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2018-06-18	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	RCV000121636	SCV000085834	not provided	not specified	2013-09-19	no assertion provided	reference population
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130497	SCV001977050	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551187	SCV004764499	likely benign	NF1-related disorder	2022-08-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).