Submissions for variant NM_000059.4(BRCA2):c.8754+3G>C

dbSNP: rs397508007

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045614	SCV000073627	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 21 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 may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 21520333, 21638052, 21769658, 23451180). ClinVar contains an entry for this variant (Variation ID: 52668). 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 retention of 46 nucleotides of intron 21 and introduces a premature termination codon (PMID: 21638052, 21769658, 23451180). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131319	SCV000186292	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-05-08	criteria provided, single submitter	clinical testing	The c.8754+3G>C intronic variant results from a G to C substitution 3 nucleotides after coding exon 20 in the BRCA2 gene. This alteration has been reported in two individuals with a personal and/or family history suggestive of hereditary breast and ovarian cancer syndrome (HBOC). In vitro RNA studies revealed that this alteration leads to monoallelic expression of a transcript retaining a part of intron 21 that is predicted to lead to a premature stop codon (Brandão RD et al. Breast Cancer Res. Treat. 2011 Oct;129(3):971-8; Thomassen M et al. Breast Cancer Res. Treat. 2012 Apr;132(3):1009-23; Colombo M et al. PLoS One, 2013 Feb;8:e57173; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Of note, this alteration is also designated as 8982+3G>C and IVS21+3G>C in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000258465	SCV000327955	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000521379	SCV000617475	likely pathogenic	not provided	2018-11-19	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8754+3G>C or IVS21+3G>C and consists of a G>C nucleotide substitution at the +3 position of intron 21 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 8982+3G>C. This variant has been observed in at least two families with breast and/or ovarian cancer (Brandao 2011, Thomassen 2012). BRCA2 c.8754+3G>C was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). The guanine (G) nucleotide that is altered is conserved in mammals. Multiple in silico models predict this variant to weaken the nearby natural donor site and to cause abnormal gene splicing. Multiple functional studies, including minigene splicing assays and RT-PCR mRNA analyses, have demonstrated that this variant induces retention of 46 nucleotides within the transcript, resulting in a predicted frameshift and truncated protein (Brandao 2011, Thomassen 2012, Colombo 2013). Based on the currently available information, we consider BRCA2 c.8754+3G>C to be a likely pathogenic variant.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000258465	SCV000743351	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000258465	SCV000744548	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131319	SCV002053557	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-19	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the +3 position of intron 21 of the BRCA2 gene. Functional RNA studies have shown that this variant causes use of a cryptic splice site 46 basepairs downstream, and introduces a premature stop (PMID: 21769658, 23451180). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in families affected with breast/ovarian cancer (PMID: 21638052, 25103822, 26833046, 27062684). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000521379	SCV002551831	likely pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000258465	SCV005046008	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1 (RNA); PM2_Supporting
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000258465	SCV000733322	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000521379	SCV001905960	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000521379	SCV001952731	pathogenic	not provided		no assertion criteria provided	clinical testing