Submissions for variant NM_000059.4(BRCA2):c.9648+1G>C

gnomAD frequency: 0.00001  dbSNP: rs730881573

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160176	SCV000210514	likely pathogenic	not provided	2022-09-28	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of a critical region, which is part of the DNA binding domain (Yang et al., 2002); Not observed at a significant frequency in large population cohorts (gnomAD); Observed in an individual referred for clinical testing for inherited cancer (Susswein et al., 2016); Also known as 9876+1G>C; This variant is associated with the following publications: (PMID: 12228710, 26681312)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000239346	SCV000296628	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817530	SCV000958096	pathogenic	Hereditary breast ovarian cancer syndrome	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 26 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). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182265). Studies have shown that disruption of this splice site alters BRCA2 gene expression (PMID: 32398771). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 26, but is expected to preserve the integrity of the reading-frame (PMID: 32398771). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Tyr3308*) have been determined to be pathogenic (PMID: 18593900, 18607349). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000160176	SCV002021541	pathogenic	not provided	2019-04-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381526	SCV002694190	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-08	criteria provided, single submitter	clinical testing	The c.9648+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 25 of the BRCA2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of 49 amino acids (Ambry internal data). A close match alteration (c.9648+1G>A) has been shown to result in the same splicing profile and has also been confirmed in trans with a pathogenic finding in this same gene in two brothers with no reported features of Fanconi anemia (Ambry internal data; Gay-Bellile M et al. Clin Genet, 2020 Apr;97:668-669). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003474824	SCV004210383	pathogenic	Familial cancer of breast	2023-02-28	criteria provided, single submitter	clinical testing