Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV003278848 | SCV004005450 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-11-20 | criteria provided, single submitter | clinical testing | The p.L3125F variant (also known as c.9373C>T), located in coding exon 24 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9373. The leucine at codon 3125 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was non-functional in a homology-directed DNA repair (HDR) assay (Richardson ME et al. Am J Hum Genet, 2021 Mar;108:458-468). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. An internal structural analysis indicates that this variant is disruptive to the protein (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Department of Pathology and Laboratory Medicine, |
RCV000503106 | SCV000592280 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The p.Leu3125Phe variant was identified in 1 of 3050 proband chromosomes (frequency: 0.00033) from individuals or families with Hereditary Breast and Ovarian cancer in a French population (Caux-Moncoutier 2011). Myriad classifies this as a “Variant of Uncertain Significance” (personal communication). This variant was also identified in two samples submitted to UMD, and was listed as an unclassified variant. The p.Leu3125Phe variant was not identified in dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, LOVD, COSMIC, ClinVar or BIC. The p.Leu3125 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster, BLOSUM) suggest that the p.Leu3125Phe variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. One out of five in silico splicing prediction programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts the creation of a potential 5’ splice site; however, the variant is not within a splicing consensus sequence and this information is not predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. |