Submissions for variant NM_001042492.3(NF1):c.8238T>G (p.Ile2746Met)

gnomAD frequency: 0.00001  dbSNP: rs779789452

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215281	SCV000275565	uncertain significance	Hereditary cancer-predisposing syndrome	2015-12-13	criteria provided, single submitter	clinical testing	The p.I2746M variant (also known as c.8238T>G), located in coding exon 57 of the NF1 gene, results from a T to G substitution at nucleotide position 8238. The isoleucine at codon 2746 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 0.003% (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.I2746M remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230134	SCV000284524	benign	Neurofibromatosis, type 1	2024-12-16	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000230134	SCV001548495	uncertain significance	Neurofibromatosis, type 1	2021-04-01	criteria provided, single submitter	clinical testing	NF1 c.8238T>G (rs779789452) is rare (<0.1%) in a large population dataset (gnomAD: 2/251440 total alleles; 0.0008%; no homozygotes) and has not been reported in the literature, to our knowledge. This variant has been reported in ClinVar (Variation ID: 231655). Three bioinformatic tools queried predict that this substitution would be tolerated, however the isoleucine residue at this position is evolutionarily conserved across most species assessed. We consider the clinical significance of NF1 c.8238T>G to be uncertain at this time.
Genome-Nilou Lab	RCV000230134	SCV002561191	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002494592	SCV002784192	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-08-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165564	SCV003895041	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-01-04	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.
PreventionGenetics, part of Exact Sciences	RCV004737350	SCV005366571	uncertain significance	NF1-related disorder	2024-06-03	no assertion criteria provided	clinical testing	The NF1 c.8238T>G variant is predicted to result in the amino acid substitution p.Ile2746Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 2 of 251,000 alleles in gnomAD. It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/231655/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.