Submissions for variant NM_000059.4(BRCA2):c.7992T>G (p.Ile2664Met)

dbSNP: rs80359800

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656803	SCV000210457	uncertain significance	not provided	2022-12-08	criteria provided, single submitter	clinical testing	Observed in individuals with personal or family history of breast and/or ovarian cancer (Laitman et al., 2011; Loizidou et al., 2017; Dorling et al., 2021; Abdel-Razeq et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8220T>G; This variant is associated with the following publications: (PMID: 20960228, 27882536, 12228710, 31131967, 33471991, 35402282, 32377563, 29884841)
Counsyl	RCV000411343	SCV000488752	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-06-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160146	SCV000600775	uncertain significance	not specified	2016-10-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566432	SCV000661272	likely benign	Hereditary cancer-predisposing syndrome	2022-01-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health	RCV000566432	SCV000683931	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 2664 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 been reported in individuals affected with breast, ovarian, or pancreatic cancer (PMID: 20960228, 27882536). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 4/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008636). This variant has been identified in 1/250460 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.
PreventionGenetics, part of Exact Sciences	RCV000656803	SCV000805773	uncertain significance	not provided	2018-01-04	criteria provided, single submitter	clinical testing
Mendelics	RCV000709332	SCV000838863	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765140	SCV000896366	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000709332	SCV000957748	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2664 of the BRCA2 protein (p.Ile2664Met). This variant is present in population databases (rs80359800, gnomAD no frequency). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 20960228, 27882536). ClinVar contains an entry for this variant (Variation ID: 182247). 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 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.
Mendelics	RCV000411343	SCV001139202	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149970	SCV003838836	uncertain significance	Breast and/or ovarian cancer	2021-09-20	criteria provided, single submitter	clinical testing
BRCAlab, Lund University	RCV000411343	SCV004243796	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing