Submissions for variant NM_000059.4(BRCA2):c.2357C>G (p.Ser786Cys)

dbSNP: rs80358501

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000773259	SCV000906890	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001315892	SCV001506486	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-04-14	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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51272). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with cysteine at codon 786 of the BRCA2 protein (p.Ser786Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000773259	SCV003848253	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).
Ambry Genetics	RCV000773259	SCV005025023	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-29	criteria provided, single submitter	clinical testing	The p.S786C variant (also known as c.2357C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 2357. The serine at codon 786 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113035	SCV000146034	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2001-10-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000499976	SCV000591803	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2, p.Ser786Cys variant was not identified in the literature, nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), LOVD, COSMIC, Clinvitae, ARUP Laboratories BRCA Mutation, MutDB, GeneInsight COGR, or BRCA Share UMD Databases. The variant was identified in dbSNP (ID: rs80358501 “With Uncertain significance allele.” The variant was also identified in Clinvar database and classified as a variant of uncertain significance by BIC and no classification was provided by Invitae; in BIC database the variant was identified 1X with unknown clinical importance. The p.Ser786 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very 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 uncertain significance.