Submissions for variant NM_000059.4(BRCA2):c.8633-2A>G

dbSNP: rs81002886

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031755	SCV001161650	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.996783
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031755	SCV000327938	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371796	SCV002684222	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-02-05	criteria provided, single submitter	clinical testing	The c.8633-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 20 in the BRCA2 gene. This alteration was identified in a cohort of German patients considered to be at increased risk for HBOC syndrome (Meisel C et al. Arch Gynecol Obstet. 2017 May;295:1227-1238). This alteration, described as c.8632-2A>G/IVS20-2A>G, was detected in a patient with early-onset ovarian cancer and a family history of breast and ovarian cancer; RT-PCR analysis demonstrated this alteration results in aberrant splicing (Chen X et al. Hum Mutat. 2006 May;27:427-35). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. 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 likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV002371796	SCV004362760	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-14	criteria provided, single submitter	clinical testing	This variant causes a A>G nucleotide substitution at the -2 position of intron 20 of the BRCA2 gene. An RNA study has shown that this variant produces two mutant transcript; a transcript that retains 93 nucleotides of intron 20 and deletes 43 nucleotides from exon 21 and a transcript that deletes 43 nucleotides from exon 21 (PMID: 16619214). Both transcripts create frameshifts and premature translation stop signals and are expected to result in absent or non-functional protein products (PMID: 16619214). A functional study has shown that this variant decreases cell viability and increases sensitivity to PARP inhibitors in mouse embryonic stem cells (PMID: 37922907). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 16619214, 28324225) and in a multifactorial analysis with segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.294, 1.060, 1.050 and 6.655, respectively (PMID: 31131967). 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.
All of Us Research Program, National Institutes of Health	RCV000031755	SCV004834561	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing	This variant causes a A>G nucleotide substitution at the -2 position of intron 20 of the BRCA2 gene. An RNA study has shown that this variant produces two mutant transcript; a transcript that retains 93 nucleotides of intron 20 and deletes 43 nucleotides from exon 21 and a transcript that deletes 43 nucleotides from exon 21 (PMID: 16619214). Both transcripts create frameshifts and premature translation stop signals and are expected to result in absent or non-functional protein products (PMID: 16619214). A functional study has shown that this variant decreases cell viability and increases sensitivity to PARP inhibitors in mouse embryonic stem cells (PMID: 37922907). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 16619214, 28324225) and in a multifactorial analysis with segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.294, 1.060, 1.050 and 6.655, respectively (PMID: 31131967). 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.
Sharing Clinical Reports Project (SCRP)	RCV000031755	SCV000054363	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2006-05-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031755	SCV000147423	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing