Submissions for variant NM_000059.4(BRCA2):c.6833T>G (p.Ile2278Ser)

dbSNP: rs1555284865

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522420	SCV000618090	uncertain significance	not provided	2017-05-08	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6833T>G at the cDNA level, p.Ile2278Ser (I2278S) at the protein level, and results in the change of an Isoleucine to a Serine (ATC>AGC). Using alternate nomenclature, this variant would be defined as BRCA2 7061T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile2278Ser was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ile2278Ser 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 Ile2278Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819360	SCV000960015	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-09-22	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2278 of the BRCA2 protein (p.Ile2278Ser). 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: 449728). 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.
Ambry Genetics	RCV001025709	SCV001187953	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-26	criteria provided, single submitter	clinical testing	The p.I2278S variant (also known as c.6833T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 6833. The isoleucine at codon 2278 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is poorly 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001025709	SCV003847498	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586755	SCV005076242	uncertain significance	not specified	2024-04-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004802123	SCV005424554	uncertain significance	BRCA2-related cancer predisposition	2024-08-06	criteria provided, single submitter	clinical testing