Total submissions: 18
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| St. |
RCV000205468 | SCV006276081 | uncertain significance | Neurofibromatosis, type 1 | 2025-06-17 | criteria provided, single submitter | clinical testing | The NF1 c.3883A>G (p.Thr1295Ala) 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 eff ect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in a large case-control study of breast cancer in 5 of 60,466 cases and 5 of 53,461 controls (PMID: 33471991). 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. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000428670 | SCV004222168 | likely benign | not specified | 2024-01-16 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. Computational tools predict this amino acid change may be benign. This variant has been seen where an alternate explanation for disease was also identified. |
| Ambry Genetics | RCV002362857 | SCV002624277 | likely benign | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2020-01-07 | 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. |
| Medical Genetics, |
RCV000205468 | SCV002567762 | likely benign | Neurofibromatosis, type 1 | 2022-08-17 | criteria provided, single submitter | clinical testing | |
| Sema4, |
RCV000165261 | SCV002527539 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-08-12 | criteria provided, single submitter | curation | |
| Baylor Genetics | RCV000205468 | SCV001482853 | uncertain significance | Neurofibromatosis, type 1 | 2020-04-10 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000428670 | SCV001361020 | uncertain significance | not specified | 2019-08-13 | criteria provided, single submitter | clinical testing | Variant summary: NF1 c.3883A>G (p.Thr1295Ala) results in a non-conservative amino acid change located in the Ras GTPase-activating domain (IPR001936) of 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 0.00011 in 251404 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (0.00011 vs 0.00021), allowing no conclusion about variant significance. c.3883A>G has been reported in the literature in individuals affected with cancer of the central nervous system (Wang_2017) and other cancers (Mandelker_2017). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (5x VUS, 1x likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Illumina Laboratory Services, |
RCV001122261 | SCV001280967 | uncertain significance | Neurofibromatosis, familial spinal | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
| Illumina Laboratory Services, |
RCV001122260 | SCV001280966 | likely benign | Neurofibromatosis-Noonan syndrome | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. |
| Illumina Laboratory Services, |
RCV000205468 | SCV001280965 | uncertain significance | Neurofibromatosis, type 1 | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
| Illumina Laboratory Services, |
RCV001122259 | SCV001280964 | uncertain significance | Café-au-lait macules with pulmonary stenosis | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
| Gene |
RCV000165261 | SCV000822096 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-08-01 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000428670 | SCV000712065 | uncertain significance | not specified | 2016-11-03 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The p.Thr1295Ala va riant in NF1 has been identified in 1 individual with clinical features of a RAS opathy disorder, but was inherited from an unaffected parent. It has been identi fied in 10/66730 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143836226). Computational prediction to ols and conservation analysis suggest that the p.Thr1295Ala variant may not impa ct the protein, though this information is not predictive enough to rule out pat hogenicity. In summary, while the clinical significance of the p.Thr1295Ala vari ant is uncertain, these data suggest that it is more likely to be benign. |
| Fulgent Genetics, |
RCV000515307 | SCV000611411 | uncertain significance | Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis | 2017-05-23 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000680330 | SCV000518631 | likely benign | not provided | 2018-01-25 | criteria provided, single submitter | clinical testing | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. |
| Labcorp Genetics |
RCV000205468 | SCV000260388 | benign | Neurofibromatosis, type 1 | 2026-02-02 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000165261 | SCV000215977 | likely benign | Hereditary cancer-predisposing syndrome | 2015-11-28 | criteria provided, single submitter | clinical testing | Insufficient evidence |
| Prevention |
RCV004737259 | SCV005355195 | uncertain significance | NF1-related disorder | 2024-05-01 | no assertion criteria provided | clinical testing | The NF1 c.3883A>G variant is predicted to result in the amino acid substitution p.Thr1295Ala. This variant has been detected in 2 individuals undergoing testing using a hereditary cancer panel and interpreted as uncertain significance (Table S5, Tsaousis et al. 2019. PubMed ID: 31159747). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/185777/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |