Submissions for variant NM_000059.4(BRCA2):c.316+2T>C

dbSNP: rs81002805

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113397	SCV001156530	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-01	reviewed by expert panel	curation	Almost complete (97%) 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).
Ambry Genetics	RCV000131849	SCV000186904	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-17	criteria provided, single submitter	clinical testing	The c.316+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 2 in the BRCA2 gene. This mutation has been detected in patients of Asian ancestry with a personal and/or family history of breast and/or ovarian cancer (LaDuca H et al. PLoS One. 2017 Feb 2;12(2):e0170843; Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376; Ambry internal data). This alteration produced coding exon 2 (also known as Exon 3) skipping in multiple minigene assays (Caputo SM et al. Oncotarget, 2018 Apr;9:17334-17348; Fraile-Bethencourt E et al. J Pathol, 2019 08;248:409-420). Other alterations impacting the same donor site (c.315+5G>A and c.316+5G>C, among others) have also been described as producing the same splice defect are considered Class 5 by a multifactorial model of variant interpretation (Caputo SM et al. Oncotarget, 2018 Apr;9:17334-17348). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759596	SCV000889017	pathogenic	not provided	2018-04-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001384949	SCV001584651	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 29707112). ClinVar contains an entry for this variant (Variation ID: 51407). Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 29707112; Invitae). This variant disrupts the PALB2 binding domain which is critical for maintenance of the DNA repair function (PMID: 16793542, 22678057, 24323938, 19609323, 19369211). While functional studies have not been performed to directly test the effect of this variant on BRCA2 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000759596	SCV001792945	pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with prostate cancer (Momozawa et al., 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 544+2T>C; This variant is associated with the following publications: (PMID: 28152038, 29707112, 30883759, 34597585, 35979650, 31214711)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001384949	SCV004241227	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.316+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site, and two predict the variant creates a cryptic 5' donor site. Publications report experimental evidence that this variant affects mRNA splicing, resulting in deletion of exon 3 (Caputo_2018, Fraile-Bethencourt_2019). The variant was absent in 249688 control chromosomes (gnomAD). c.316+2T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Caputo_2018, Inagaki-Kawata_2020). The following publications have been ascertained in the context of this evaluation (PMID: 29707112, 30883759, 33067557). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV004566818	SCV005059008	pathogenic	Familial cancer of breast	2024-03-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113397	SCV000146564	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-06-20	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162368	SCV002758118	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research