Submissions for variant NM_000059.4(BRCA2):c.8450G>T (p.Cys2817Phe)

gnomAD frequency: 0.00001  dbSNP: rs786201992

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164566	SCV000215224	likely benign	Hereditary cancer-predisposing syndrome	2020-02-10	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229582	SCV000283342	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-12	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 2817 of the BRCA2 protein (p.Cys2817Phe). This variant is present in population databases (rs786201992, gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 185196). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985253	SCV000600805	uncertain significance	not provided	2020-12-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164566	SCV000689127	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 2817 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown this variant does not impact homology-directed DNA repair activity (PMID: 33609447). This variant has been detected in at least 3 individuals affected with breast cancer (PMID: 25186627, 33471991; Leiden Open Variation Database DB-ID BRCA2_008669; Color internal data). This variant also has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database. This variant has been identified in 1/251412 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506092	SCV000918860	uncertain significance	not specified	2018-01-15	criteria provided, single submitter	clinical testing	Variant summary: The c.8450G>T (p.Cys2817Phe) in BRCA2 gene is a missense variant involves a highly conserved nucleotide and 5/5 in silico tools used predict deleterious outcome. The variant is located within the second OB fold (OB2) functional domain, however no functional studies confirming an effect of this change on the protein function were published at the time of evaluation. The variant is present in the control population dataset of gnomAD (0.000004; 1/246186 chrs tested), which does not exceed the maximal expected allele frequency for a disease causing allele in BRCa2 gene (0.00075). The variant has been reported in at least one affected individual with personal and family history of BrC, who also carried a pathogenic variant in BRCA1 (Tung_2015) as well as in healthy controls (FlOSSIES db), and is cited as VUS by a reputable databases/clinical laboratories. Taken together,due to lack of segregatiaon data for the reported affected individuals, the variant was classified as VUS, until new information becomes available.
Sema4, Sema4	RCV000164566	SCV002531946	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-19	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003234771	SCV003932764	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	For the BRCA2 variant, The sequence change replaces cysteine with phenylalanine at codon 2817 of the BRCA2 protein (p.Cys2817Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 185196). In-silico simulation software to predict the effect of missense changes on protein structure and function showed (SIFT: deleterious, PolyPhen-2: probably damaging) 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. Pathogenic variants in the BRCA2 gene are associated with hereditary breat/ovarian cancer syndrome. Genetic counseling is recommended.
Baylor Genetics	RCV003462142	SCV004213598	uncertain significance	Familial cancer of breast	2023-09-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003234771	SCV004846023	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 2817 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown this variant does not impact homology-directed DNA repair activity (PMID: 33609447). This variant has been detected in at least 3 individuals affected with breast cancer (PMID: 25186627, 33471991; Leiden Open Variation Database DB-ID BRCA2_008669; Color internal data). This variant also has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database. This variant has been identified in 1/251412 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.
BRCAlab, Lund University	RCV003234771	SCV004243818	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing