Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000817582 | SCV000958151 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2018-09-04 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BRCA2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 2478 of the BRCA2 protein (p.Leu2478Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. |
| Ambry Genetics | RCV001026433 | SCV001188813 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-11-28 | criteria provided, single submitter | clinical testing | The p.L2478F variant (also known as c.7434A>C) results from an A to C substitution at nucleotide position 7434, which is the second to last nucleotide of coding exon 13. The leucine at codon 2478 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001194443 | SCV001364005 | uncertain significance | not specified | 2019-04-15 | criteria provided, single submitter | clinical testing | Variant summary: BRCA2 c.7434A>C (p.Leu2478Phe) 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 was absent in 250528 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.7434A>C, has been reported in the literature in individuals affected with breast cancer (Tung_2016). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |