Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000129823 | SCV000184637 | likely benign | Hereditary cancer-predisposing syndrome | 2015-06-08 | criteria provided, single submitter | clinical testing | Insufficient or Conflicting Evidence |
| Labcorp Genetics |
RCV000459107 | SCV000542145 | benign | Neurofibromatosis, type 1 | 2025-02-02 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001420819 | SCV001623199 | benign | not specified | 2021-04-25 | criteria provided, single submitter | clinical testing | Variant summary: NF1 c.888+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.6e-05 in 248134 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.888+5G>A in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (TP53 c.742C>T, p.Arg248Trp), providing supporting evidence for a benign role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. |
| Gene |
RCV001553065 | SCV001773866 | likely benign | not provided | 2020-02-19 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002371976 | SCV002685507 | likely benign | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2019-11-09 | 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. |