Submissions for variant NM_000059.4(BRCA2):c.7282T>G (p.Leu2428Val)

dbSNP: rs1057521856

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001981420	SCV002223240	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2428 of the BRCA2 protein (p.Leu2428Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 34413315). ClinVar contains an entry for this variant (Variation ID: 1443800). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282662	SCV002572214	uncertain significance	not specified	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7282T>G (p.Leu2428Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251242 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7282T>G has been reported in the literature in at least one individual affected with Breast/Ovarian Cancer (Herzog_2021). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004010966	SCV004844387	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 2428 of the BRCA2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004946923	SCV005551972	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-08	criteria provided, single submitter	clinical testing	The p.L2428V variant (also known as c.7282T>G), located in coding exon 13 of the BRCA2 gene, results from a T to G substitution at nucleotide position 7282. The leucine at codon 2428 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.