Submissions for variant NM_000059.4(BRCA2):c.9648G>A (p.Leu3216=)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002376498	SCV002690697	uncertain significance	Hereditary cancer-predisposing syndrome	2020-05-07	criteria provided, single submitter	clinical testing	The c.9648G>A variant (also known as p.L3216L), located in coding exon 25 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9648. This nucleotide substitution does not change the at codon 3216. However, this change occurs in the last base pair of coding exon 25, which makes it likely to have some effect on normal mRNA splicing. This variant has been identified in a healthy individual with a family history of breast cancer who also carried a RAD51C missense variant (Ahlborn LB et al. Fam. Cancer, 2015 Mar;14:129-33). This nucleotide position is well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to weaken the efficiency of the native splice donor site, but is not predicted to have a deleterious effect on this splice donor site by BDGP; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV005055458	SCV005689602	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2025-02-04	criteria provided, single submitter	clinical testing	The following ACMG criteria have been used in classification: PM2_SUP; PVS1_MOD (RNA)
Labcorp Genetics (formerly Invitae), Labcorp	RCV005097356	SCV005835607	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change affects codon 3216 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. This variant also falls at the last nucleotide of exon 26, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with an individual with a family history of breast cancer who also carried a pathogenic variant in a different gene (PMID: 25154786). ClinVar contains an entry for this variant (Variation ID: 1767663). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.