Submissions for variant NM_000059.4(BRCA2):c.9206G>T (p.Cys3069Phe)

dbSNP: rs587782091

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130600	SCV000185474	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-31	criteria provided, single submitter	clinical testing	The p.C3069F variant (also known as c.9206G>T), located in coding exon 23 of the BRCA2 gene, results from a G to T substitution at nucleotide position 9206. The cysteine at codon 3069 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was reported in 1 of 989 German breast and/or ovarian cancer families (Meindl, A et al. Int J Cancer. 2002 Feb 1;97(4):472-80). Additionally, this alteration has been previously identified in an individual from a North American cohort of individuals with early onset colon cancer (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This variant was identified amongst 81 Egyptian patients with breast cancer (Azim HA et al. Oncol Ther, 2023 Dec;11:445-459). This variant was also classified as pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat, 2019 Sep;40:1557-1578). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205419	SCV000261116	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-30	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 3069 of the BRCA2 protein (p.Cys3069Phe). This variant is present in population databases (rs587782091, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer and/or clinical features of BRCA2-related conditions (PMID: 11802209, 34597585). This variant is also known as 9434G>T. ClinVar contains an entry for this variant (Variation ID: 141897). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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	RCV000215969	SCV000279521	uncertain significance	not provided	2018-05-04	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9206G>T at the cDNA level, p.Cys3069Phe (C3069F) at the protein level, and results in the change of a Cysteine to a Phenylalanine (TGT>TTT). Using alternate nomenclature, this variant has been previously published as BRCA2 9434G>T. This variant was observed in at least one individual with a personal and family history of breast cancer (Meindl 2002) as well as a male with mismatch repair-proficient cecal cancer who also harbored a pathogenic SMAD4 variant (Pearlman 2017). BRCA2 Cys3069Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Cys3069Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000215969	SCV002046264	uncertain significance	not provided	2020-10-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130600	SCV002532013	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-10	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003998067	SCV004814339	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-04-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567120	SCV005059096	uncertain significance	Familial cancer of breast	2024-01-23	criteria provided, single submitter	clinical testing