Submissions for variant NM_001042492.3(NF1):c.6801A>G (p.Ile2267Met)

dbSNP: rs876659381

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219416	SCV000275769	uncertain significance	Hereditary cancer-predisposing syndrome	2015-05-18	criteria provided, single submitter	clinical testing	The p.I2267M variant (also known as c.6801A>G), located in coding exon 45 of the NF1 gene, results from an A to G substitution at nucleotide position 6801. The isoleucine at codon 2267 is replaced by methionine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55,000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.I2267M remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001318207	SCV001508899	uncertain significance	Neurofibromatosis, type 1	2024-05-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2246 of the NF1 protein (p.Ile2246Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 231810). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001318207	SCV002560999	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558522	SCV005048338	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-06-22	criteria provided, single submitter	clinical testing	The c.6738A>G (p.I2246M) alteration is located in exon 44 (coding exon 44) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 6738, causing the isoleucine (I) at amino acid position 2246 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004547545	SCV004715121	uncertain significance	NF1-related disorder	2023-11-13	no assertion criteria provided	clinical testing	The NF1 c.6801A>G variant is predicted to result in the amino acid substitution p.Ile2267Met. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.