Submissions for variant NM_001042492.3(NF1):c.2032C>G (p.Pro678Ala)

gnomAD frequency: 0.00013  dbSNP: rs758691069

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213376	SCV000275676	uncertain significance	Hereditary cancer-predisposing syndrome	2015-05-07	criteria provided, single submitter	clinical testing	The p.P678A variant (also known as c.2032C>G), located in coding exon 18 of the NF1 gene, results from a C to G substitution at nucleotide position 2032. The proline at codon 678 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is highly 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.P678A remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464265	SCV000542220	benign	Neurofibromatosis, type 1	2025-02-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000213376	SCV002527442	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265694	SCV002547945	uncertain significance	not specified	2022-05-05	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.2032C>G (p.Pro678Ala) 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 1.2e-05 in 250606 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2032C>G in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000464265	SCV002561985	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV002293429	SCV002586801	uncertain significance	not provided	2022-04-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25486365)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000464265	SCV004171440	uncertain significance	Neurofibromatosis, type 1	2023-11-28	criteria provided, single submitter	clinical testing	The NF1 c.2032C>G (p.Pro678Ala) change has a maximum subpopulation frequency of 0.020% 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. 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	RCV004558520	SCV005048609	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-12-09	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.