Submissions for variant NM_000059.4(BRCA2):c.8332-1G>T

dbSNP: rs397507979

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164696	SCV000215364	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-19	criteria provided, single submitter	clinical testing	The c.8332-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 18 of the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration was observed in an individuals with a personal and family history of early onset breast cancer (Becker AA et al. Breast Cancer Res. Treat., 2012 Aug;135:167-75; Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same donor/acceptor site (c.8332-1G>A) has been shown to have a similar impact on splicing (Menéndez M et al. Breast Cancer Res Treat, 2012 Apr;132:979-92). 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 interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000258264	SCV000327873	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586321	SCV000695145	likely pathogenic	Hereditary breast ovarian cancer syndrome	2017-05-26	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.8332-1G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict a weakening of the canonical splice donor site while 3/5 splice prediction tools predict the variant to activate a cryptic splice donor site. However, these predictions have yet to be confirmed by functional studies. The variant of interest has not been found in a large, broad control population, ExAC in 121260 control chromosomes. This variant was reported in one study in a BC patient with extensive BC history (Becker_Breast Cancer Res Treat_2012). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000586321	SCV001375007	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-07-25	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 18 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered 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 clinical features of BRCA2-related conditions (PMID: 22729890, 29446198, 30199306). ClinVar contains an entry for this variant (Variation ID: 185300). Studies have shown that disruption of this splice site results in deletion of 14 nucleotides of exon 19, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 21735045). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001311842	SCV002073981	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, leading to the in-frame deletion of exon 19, which is located in the critical DSS1 contacting residue of the DNA binding domain (Yang 2002); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as 8560-1G>T; Observed in individuals with a personal or family history of breast cancer in published literature (Becker 2012, Abulkhair 2018); This variant is associated with the following publications: (PMID: 30199306, 22729890, 29446198)
Color Diagnostics, LLC DBA Color Health	RCV000164696	SCV004362745	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-16	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the -1 position of intron 18 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. A functional RNA study reported that a variant impacting the same splice site, c.8332-1G>C, causes a 14 nucleotide deletion in exon 19 and is expected to result in a frameshift and premature translation stop signal (PMID: 21735045). This variant has been reported in at least two individuals affected with breast cancer and an individual affected with pancreatic cancer (PMID: 22729890, 30199306, 33471991, 35171259). 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 Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000258264	SCV004833244	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-11	criteria provided, single submitter	clinical testing	The c.8332-1G>T variant in the BRCA2 gene is located at the canonical splice site of intron 18 and is predicted to inflict acceptor loss (SpliceAI delta score: 0.99), resulting in alternative splicing and disrupted protein product. The variant has been reported in 3 unrelated individuals with breast/ pancreatic cancer (PMID: 29297111, 35171259, 22729890). Experimental analysis of cDNA showed that this variant abolishes the natural 3? splice site of exon 19 and leads to the activation of a cryptic splice site 14 bp downstream. The mutated transcript shows a 14-bp deletion at the beginning of exon 19. This change is predicted to generate a truncated protein (p.Ile2778Tyrfs*15) (PMID: 21735045). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar (ID: 185300). The variant is absent in the general population database (gnomAD). Therefore, the c.8332-1G>T variant of BRCA2 has been classified as pathogenic.