Submissions for variant NM_000059.4(BRCA2):c.1151C>G (p.Ser384Cys)

dbSNP: rs41293475

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484001	SCV000572198	uncertain significance	not provided	2017-11-08	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.1151C>G at the cDNA level, p.Ser384Cys (S384C) at the protein level, and results in the change of a Serine to a Cysteine (TCC>TGC). Using alternate nomenclature, this variant would be defined as BRCA2 1379C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser384Cys was not observed in large population cohorts (Lek 2016). Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser384Cys occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Ser384Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069889	SCV001235086	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-08-27	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 384 of the BRCA2 protein (p.Ser384Cys). 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: 422677). 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. 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.
Molecular Endocrinology Laboratory, Christian Medical College	RCV001788234	SCV002030312	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV003157590	SCV003849875	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).