Submissions for variant NM_000059.4(BRCA2):c.7008-5T>C

dbSNP: rs397507380

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004566775	SCV004101437	likely benign	BRCA2-related cancer predisposition	2024-06-11	reviewed by expert panel	curation	The c.7008-5T>C variant is an intronic variant occurring in intron 13 of the BRCA2 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). This BRCA2 intronic variant is outside of the native donor and acceptor 1,2 splice sites, and the SpliceAI predictor score of 0.12 indicates that impact on splicing is unclear (score range 0.10-0.20) (PP3 and BP4 not met). This is an intronic variant, and mRNA experimental analysis indicates no impact on splicing (PMID: 31191615), considered strong evidence against pathogenicity (BP7_Strong (RNA)). In summary, this variant meets the criteria to be classified as a Likely benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, BP7_Strong (RNA)).
GeneDx	RCV000587746	SCV000321481	uncertain significance	not provided	2018-07-30	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.7008-5T>C or IVS13-5T>C and consists of a T>C nucleotide substitution at the -5 position of intron 13 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 7236-5T>C. In silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown.? This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 c.7008-5T>C was not observed in large population cohorts. Based on currently available evidence, it is unclear whether BRCA2 c.7008-5T>C is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456457	SCV000549851	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255121	SCV000600729	uncertain significance	not specified	2016-09-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575836	SCV000668821	likely benign	Hereditary cancer-predisposing syndrome	2021-03-15	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.
Color Diagnostics, LLC DBA Color Health	RCV000575836	SCV000689025	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-25	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the -5 position of intron 13 of the BRCA2 gene. A RNA study reported that this variant did not impact splicing in a minigene splicing assay (PMID: 31191615). This variant has been detected in individuals affected with BRCA2-associated cancers and relevant family history (Color internal data). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587746	SCV000695026	uncertain significance	not provided	2016-11-07	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.7008-5T>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 120432 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Sema4, Sema4	RCV000575836	SCV002536291	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-07	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000031660	SCV000054267	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-03	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357070	SCV001552406	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 c.7008-5T>C variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs397507380) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics, and four other submitters), and in LOVD 3.0 (1x as uncertain). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.7008-5T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.