Submissions for variant NM_001042492.3(NF1):c.3484A>G (p.Met1162Val)

gnomAD frequency: 0.00004  dbSNP: rs773968270

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206616	SCV000259797	likely benign	Neurofibromatosis, type 1	2025-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000492521	SCV000581281	uncertain significance	Hereditary cancer-predisposing syndrome	2015-06-25	criteria provided, single submitter	clinical testing	The p.M1162V variant (also known as c.3484A>G), located in coding exon 26 of the NF1 gene, results from an A to G substitution at nucleotide position 3484. The methionine at codon 1162 is replaced by valine, 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 55000alleles 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.M1162Vremains unclear.
Sema4, Sema4	RCV000492521	SCV002527514	likely benign	Hereditary cancer-predisposing syndrome	2021-05-30	criteria provided, single submitter	curation
Ambry Genetics	RCV002336555	SCV002618605	benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-09-30	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.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153478	SCV003843527	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357245	SCV001552659	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NF1 p.M1162V variant was identified in one of 200 proband chromosomes (frequency: 0.005) from individuals or families with a clinical diagnosis of Neurofibromatosis type 1 (NF1) (Wu-Chou_2018_PMID:30290804). The variant was also identified in one of 34 proband chromosomes (frequency: 0.029) from individuals with a clinical diagnosis of Noonan syndrome (Koh_2019_PMID:30784236). This patient inherited the p.M1162V variant from his father and both did not meet clinical criteria for NF1 (Koh_2019_PMID:30784236). The variant was also identified in dbSNP (ID: rs773968270) and in ClinVar (conflicting interpretations of pathogenicity; classified as uncertain significance by Ambry Genetics and likely benign by Invitae for Neurofibromatosis type 1 and Hereditary cancer-predisposing syndrome). The variant was not identified in COSMIC or LOVD 3.0. The variant was identified in control databases in 32 of 282690 chromosomes at a frequency of 0.000113 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 31 of 19924 chromosomes (freq: 0.001556) and European (non-Finnish) in 1 of 129068 chromosomes (freq: 0.000008), but was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), Other, or South Asian populations. The p.Met1162 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV003150978	SCV003839764	likely benign	not specified	2022-07-13	no assertion criteria provided	clinical testing