Submissions for variant NM_000059.4(BRCA2):c.316+5G>A

dbSNP: rs81002840

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077294	SCV001156532	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-01	reviewed by expert panel	curation	Almost complete (94%) skipping of exon 3 (r.68_316del) in a minigene splicing assay. Molecular consequence is the same as other variants designated as pathogenic as determined by multifactorial likelihood analysis (PMID: 29707112). Specifically, pathogenic consequence of the in-frame transcript without exon 3 has been shown in another family with a deletion of this exon, by co-segregation analysis with LR >1300:1 in favour of pathogenicity (PMID: 29707112).
Invitae	RCV000044130	SCV000072143	pathogenic	Hereditary breast ovarian cancer syndrome	2022-10-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.316+5G nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18424508, 21120943, 21939546, 22505045, 24549055, 29707112). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 21769658, 29707112; Invitae). ClinVar contains an entry for this variant (Variation ID: 51409). This variant has been observed in individual(s) with breast and ovarian cancer (PMID: 21120943, 21769658, 26207792, 29470806). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 3 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.
Ambry Genetics	RCV000216220	SCV000273756	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-11	criteria provided, single submitter	clinical testing	The c.316+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 2 in the BRCA2 gene. This mutation has been identified in kindreds with hereditary breast and ovarian cancer (Muller D et al. BMC Med. Genet. 2011; 12:121) as well as in one family with members diagnosed with various types of cancers, including early onset breast cancer, prostate cancer, abdominal cancer, and basal cell carcinoma (Thomassen M et al. Breast Cancer Res. Treat. 2012 Apr;132(3):1009-23). Additionally, functional analysis has demonstrated that this alteration leads to a skipping of coding exon 2, a region with a high degree of evolutionary conservation and importance for protein function (Thomassen M et al. Breast Cancer Res.Treat. 2012 Apr; 132(3):1009-23). Of note, this alteration is also designated as IVS3+5G>A in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000486888	SCV000568446	likely pathogenic	not provided	2016-08-15	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.316+5G>A or IVS3+5G>A and consists of a G>A nucleotide substitution at the +5 position of intron 3 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 544+5G>A. This variant was observed in several individuals with a personal and family history of breast and/or ovarian cancer (Thomassen 2012, Decker 2013). Multiple in silico models predict, and RT-PCR analysis confirm, that this variant causes and in-frame deletion of exon 3 (Thomassen 2012, Decker 2013). Although an alternate isoform of BRCA2 lacking exon 3 has been described in multiple tissues, the level of this transcript is significantly more abundant in those harboring BRCA2 544+5G>A, and other similar variants that also result in exon 3 skipping (Muller 2011, Thomassen 2012). BRCA2 c.316+5G>A 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 guanine (G) nucleotide that is altered is conserved across species. Based on the currently available evidence, we consider BRCA2 c.316+5G>A to be a likely pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486888	SCV000600541	likely pathogenic	not provided	2017-06-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000044130	SCV000838728	likely pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216220	SCV000906876	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-25	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of intron 3 of the BRCA2 gene. RNA studies have shown that this variant causes in-frame skipping of exon 3, resulting in partial loss of the PALB2 binding site. This variant has been reported in individuals affected with breast or ovarian cancer, including 1 male individual and 1 individual affected with early-onset breast cancer (PMID: 21769658, 31512090). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Sema4, Sema4	RCV000216220	SCV002533766	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-09-03	criteria provided, single submitter	curation
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003338395	SCV004048516	pathogenic	Familial cancer of breast		criteria provided, single submitter	clinical testing	This variant has been observed in several individuals affected with breast and ovarian cancer (Thomassen M et al). In addition, this variant segregates with breast and prostate cancer in one family (Caputo SM et al). This variant has been reported to the ClinVar database as pathogenic. The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This sequence change falls in intron 3 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein, but it affects a nucleotide within the consensus splice site of the intron. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (Buratti E et al). Experimental studies have shown that this sequence change causes skipping of exon 3 of the BRCA2 mRNA (Thomassen M et al). Skipping of exon 3 results in in-frame deletion of 83 amino acid residues from the BRCA2 protein partially including the PALB2 binding domain, which is important for DNA repair activity of the BRCA2 protein (Oliver AW et al). For these reasons, this variant has been classified as pathogenic.
Baylor Genetics	RCV003338395	SCV004212925	pathogenic	Familial cancer of breast	2021-08-02	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000486888	SCV004225598	pathogenic	not provided	2023-02-21	criteria provided, single submitter	clinical testing	PP1, PP3, PP5, PM2, PS3, PVS1_strong
Sharing Clinical Reports Project (SCRP)	RCV000077294	SCV000109091	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-09-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077294	SCV000146565	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735537	SCV000863675	pathogenic	Breast and/or ovarian cancer	2013-04-04	no assertion criteria provided	clinical testing
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332098	SCV004040595	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research