Submissions for variant NM_001042492.3(NF1):c.2581G>C (p.Ala861Pro)

gnomAD frequency: 0.00001  dbSNP: rs768425956

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222895	SCV000273861	uncertain significance	Hereditary cancer-predisposing syndrome	2015-08-11	criteria provided, single submitter	clinical testing	The p.A861P variant (also known as c.2581G>C), located in coding exon 21 of the NF1 gene, results from a G to C substitution at nucleotide position 2581. The alanine at codon 861 is replaced by proline, 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 0.004% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. However, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.A861P remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231109	SCV000284413	benign	Neurofibromatosis, type 1	2024-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000413260	SCV000491383	likely benign	not provided	2020-08-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778805	SCV002015057	uncertain significance	not specified	2021-10-25	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.2581G>C (p.Ala861Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250864 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2581G>C has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (Koczkowska_2018), and breast cancer (Weitzel_2019). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2 VUS, 1 likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000222895	SCV002527465	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-19	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000231109	SCV002584712	uncertain significance	Neurofibromatosis, type 1	2022-10-06	criteria provided, single submitter	clinical testing	The NF1 c.2581G>C (p.Ala861Pro) missense change has a maximum subpopulation frequency of 0.017% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. A case-control study of 1054 BRCA-mutation–negative women with hereditary breast cancer and 1199 controls indicated that the variant is present in approximately equal proportions of cases and controls with an odds ratio of 1.1 (PMID: 31206626). To our knowledge, this variant has not been reported in individuals with Neurofibromatosis type 1. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Ambry Genetics	RCV003165557	SCV003897026	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-03-06	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.