Submissions for variant NM_000059.4(BRCA2):c.9290G>A (p.Cys3097Tyr)

dbSNP: rs730881570

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160167	SCV000210502	uncertain significance	not provided	2014-09-09	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9290G>A at the cDNA level, p.Cys3097Tyr (C3097Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Cys3097Tyr 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 Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Cys3097Tyr occurs at a position that is moderately conserved through mammals and is located in the DNA-binding domain (Borg 2010). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Cys3097Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206642	SCV000259428	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-14	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. 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. ClinVar contains an entry for this variant (Variation ID: 182261). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 3097 of the BRCA2 protein (p.Cys3097Tyr).
MGZ Medical Genetics Center	RCV002288678	SCV002581777	uncertain significance	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP4, PM2_SUP
Ambry Genetics	RCV002372041	SCV002686543	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-02	criteria provided, single submitter	clinical testing	The p.C3097Y variant (also known as c.9290G>A), located in coding exon 24 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9290. The cysteine at codon 3097 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV002288678	SCV004211849	uncertain significance	Familial cancer of breast	2023-10-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998454	SCV004846152	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-04	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 3097 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 not been identified 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.