Submissions for variant NM_000059.4(BRCA2):c.7992T>A (p.Ile2664=)

gnomAD frequency: 0.00001  dbSNP: rs80359800

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000494843	SCV000579007	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Invitae	RCV001082574	SCV000073389	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000589588	SCV000210455	uncertain significance	not provided	2017-11-09	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.7992T>A at the DNA level. Using alternate nomenclature, this variant would be defined as BRCA2 8220T>A. Although the variant is silent at the coding level, preserving an Isoleucine at codon 2664, it has been demonstrated to cause abnormal splicing. However, the splicing error has been characterized as having a partial, or leaky, effect, with some full length transcript also being produced (Th?ry 2011, Houdayer 2012). BRCA2 c.7992T>A has been reported in a patient with bilateral breast cancer and a family history of early onset breast cancer (Th?ry 2011). BRCA2 c.7992T>A was not observed at a significant allele frequency in large population cohorts (Lek 2016). The nucleotide which is altered, a thymine (T) at base 7992, is conserved among mammals. Based on currently available information, it is unclear whether BRCA2 c.7992T>A is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000163206	SCV000213729	likely benign	Hereditary cancer-predisposing syndrome	2018-08-15	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045376	SCV000695118	uncertain significance	not specified	2019-09-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7992T>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools via ALAMUT predict no significant impact on normal splicing. Another in-silico tool for assessing the pathogenicity of synonymous variants, namely TraP (Transcript-inferred Pathogenicity, Gelfman_2017) predicts that this variant is Benign. However, splicing functional assays demonstrated the variant increases skipping of exon 18 (Thery_2011, Houdayer_2012, Fraile-Bethencourt_2017), however It is complex to interpret the role of variants with partial splicing anomalies in HBOC under the clinical perspective. The variant allele was found at a frequency of 3.2e-05 in 250460 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.7992T>A, has been reported in the literature in one individual affected with breast cancer (Thery_BRCA2_EJHG_2011). The data does not allow any conclusion about variant significance. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=2, likely benign, n=2) and one expert panel (ENIGMA) classified this variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign
Color Diagnostics, LLC DBA Color Health	RCV000163206	SCV000910870	likely benign	Hereditary cancer-predisposing syndrome	2015-12-04	criteria provided, single submitter	clinical testing
Mendelics	RCV000494843	SCV001139201	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000045376	SCV002551724	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589588	SCV002774116	likely benign	not provided	2021-08-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000589588	SCV004226425	uncertain significance	not provided	2022-03-07	criteria provided, single submitter	clinical testing	BP6, BP7, PS3_supporting
PreventionGenetics, part of Exact Sciences	RCV003944964	SCV004762829	likely benign	BRCA2-related condition	2020-12-27	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353768	SCV000592167	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ile2664Ile has been identified in UMD (6X) and the BIC (1X) databases. It is listed in dbSNP database coming from a “clinical source” (ID#: rs80359800) with a “global minor allele frequency of less than 0.001 (1000 genomes). This variant is not expected to have clinical significance because it does not alter an amino acid residue, however it has been suggested to induce incomplete skipping of exon 18 of BRCA2 detected by minigene and in vivo assays (Thery 2011); yet in–silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts no change in the splice site prediction score. In summary, the clinical significance of this variant cannot be determined with certainty at this time. Therefore this variant is a variant of unknown significance (VUS).
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735606	SCV000863744	uncertain significance	Breast and/or ovarian cancer	2015-08-07	no assertion criteria provided	clinical testing
King Laboratory, University of Washington	RCV001171450	SCV001251361	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2; Hereditary breast ovarian cancer syndrome	2019-09-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589588	SCV001955500	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589588	SCV001971515	likely benign	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000494843	SCV004243795	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing