Submissions for variant NM_000059.4(BRCA2):c.1282C>A (p.Leu428Ile)

dbSNP: rs547590567

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167165	SCV000217998	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-28	criteria provided, single submitter	clinical testing	The p.L428I variant (also known as c.1282C>A), located in coding exon 9 of the BRCA2 gene, results from a C to A substitution at nucleotide position 1282. The leucine at codon 428 is replaced by isoleucine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508325	SCV000600473	uncertain significance	not specified	2017-05-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765131	SCV000896357	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000816899	SCV000957428	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 428 of the BRCA2 protein (p.Leu428Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 187437). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
GeneDx	RCV001565649	SCV001789034	uncertain significance	not provided	2021-04-14	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 1510C>A
University of Washington Department of Laboratory Medicine, University of Washington	RCV000167165	SCV003849969	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003234772	SCV003932727	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with isoleucine at codon 428 of the BRCA2 protein (p.Leu428Ile). This variant is not present in population databases (gnomAD). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 187437) with 4 submissions, two stars, and no conflict. In-silico prediction algorithms show benign computational verdict based on 9 benign predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, MVP, MutationTaster, PrimateAI, REVEL and SIFT vs 1 pathogenic prediction from M-CAP and the position is not strongly conserved, and there is a small physicochemical difference between leucine and isoleucine. The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Therefore, it has been classified as a Variant of Uncertain Significance. Pathogenic/likely pathogenic variants in the BRCA2 gene are known to cause hereditary breast/ovarian cancer syndrome (OMIM 612555).