Submissions for variant NM_000059.4(BRCA2):c.632-3_632-2del

dbSNP: rs431825341

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218264	SCV000277266	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-01	criteria provided, single submitter	clinical testing	The c.632-3_632-2delCA intronic variant, located upstream of coding exon 7 in the BRCA2 gene, results from a deletion of two nucleotides at the c.632-3 and c.632-2 positions. In silico splice site analysis for this alteration is inconclusive. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). These nucleotide positions are well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233601	SCV000283289	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 25381700). ClinVar contains an entry for this variant (Variation ID: 96837). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (Invitae). 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	RCV000255648	SCV000321448	uncertain significance	not provided	2016-04-12	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.632-3_632-2delCA or IVS7-3_IVS7-2delCA and consists of a deletion of two nucleotides at the -2 and -3 position of intron 7 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 860-3_860-2delCA. The normal sequence with the bases that are deleted in brackets is ctta[ca]gTCA, where the capital letters are exonic and lowercase are intronic. Multiple in silico models predict this variant to destroy the nearby natural acceptor site and to possibly cause abnormal gene splicing; 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 pathogenic or benign. BRCA2 c.632-3_632-2delCA was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The nucleotides that are deleted are conserved across species. Based on currently available information, it is unclear whether BRCA2 c.632-3_632-2delCA is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000218264	SCV000906018	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	This variant deletes two nucleotides at the -3 and -2 position in intron 7 of the BRCA2 gene. An RNA study using a minigene assay has shown this variant does not impact splicing (PMID: 36446827). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 35220195). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255648	SCV001133861	uncertain significance	not provided	2018-09-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460758	SCV004216077	uncertain significance	Familial cancer of breast	2023-06-14	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000082958	SCV000115032	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2007-11-21	no assertion criteria provided	clinical testing