Submissions for variant NM_001042492.3(NF1):c.2570A>G (p.Asn857Ser)

gnomAD frequency: 0.00003  dbSNP: rs1060500299

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465212	SCV000542074	benign	Neurofibromatosis, type 1	2024-10-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002318506	SCV000670477	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-09-12	criteria provided, single submitter	clinical testing	The p.N857S variant (also known as c.2570A>G), located in coding exon 21 of the NF1 gene, results from an A to G substitution at nucleotide position 2570. The asparagine at codon 857 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported with a carrier frequency of 1 in 7051 unselected breast cancer patients and 0 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is not 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 this alteration remains unclear.
GeneDx	RCV001753863	SCV002005464	uncertain significance	not provided	2023-04-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a child with caf-au-lait macules and their unaffected parent (Koczkowska et al., 2018); Observed in individuals with breast cancer (Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 10678181, 29872168, 27069254, 23460398, 25486365, 2121369, 29290338, 30287823)
Genome-Nilou Lab	RCV000465212	SCV002562058	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002480345	SCV002786246	likely benign	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2024-06-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114578	SCV003800698	uncertain significance	not specified	2023-01-16	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.2570A>G (p.Asn857Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250832 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2570A>G has been reported in the literature in individuals affected with NF1 disease or breast cancer. 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004737493	SCV005364480	uncertain significance	NF1-related disorder	2024-09-20	no assertion criteria provided	clinical testing	The NF1 c.2570A>G variant is predicted to result in the amino acid substitution p.Asn857Ser. This variant has been reported in an individual with multiple café au lait macules (CALMs) who inherited the variant from his apparently unaffected mother (Supplemental Data, Koczkowska et al. 2018. PubMed ID: 29290338). It has also been reported in an individual with breast cancer as part of a large case-control study in the Japanese population (Supplementary Table 1, Momozawa et al. 2018. PubMed ID: 30287823). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/404494/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.