Submissions for variant NM_000059.4(BRCA2):c.8714A>G (p.Tyr2905Cys)

gnomAD frequency: 0.00002  dbSNP: rs431825368

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460625	SCV000549554	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-10-11	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 96871). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs431825368, gnomAD 0.01%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2905 of the BRCA2 protein (p.Tyr2905Cys). 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.
GeneDx	RCV000479199	SCV000566552	uncertain significance	not provided	2015-05-11	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8714A>G at the cDNA level, p.Tyr2905Cys (Y2905C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). Using alternate nomenclature, this variant would be defined as BRCA2 8942A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Tyr2905Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr2905Cys occurs at a position that is conserved across species and is located in the DNA binding domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA2 Tyr2905Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000584302	SCV000689147	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-28	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 2905 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251312 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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	RCV000584302	SCV001179422	likely benign	Hereditary cancer-predisposing syndrome	2022-01-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV004804093	SCV004846060	uncertain significance	BRCA2-related cancer predisposition	2024-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 2905 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have shown this variant does not impact cell viability or increase drug sensitivity to cisplatin or PARP inhibitors (PMID: 32444794, 37922907), but does increase sensitivity to CBDCA (PMID: 32444794). This variant has not been reported in individuals affected with BRCA2-related cancer in the literature, but has been reported in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008698). This variant has been identified in 4/251312 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Sharing Clinical Reports Project (SCRP)	RCV000082992	SCV000115066	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing