ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7008-2A>T (rs81002823)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113689 SCV000282248 pathogenic Breast-ovarian cancer, familial 2 2016-04-03 reviewed by expert panel curation Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.7008_7435del, r.7008_7017del, and r.7008_7253del transcripts (encoding predicted non-functional proteins).
Ambry Genetics RCV000220759 SCV000275758 pathogenic Hereditary cancer-predisposing syndrome 2017-11-30 criteria provided, single submitter clinical testing ONLY INCLUDE IF PT HAS BOTH c.7008-2A>T and c.631G>A (p.V211I) BRCA2 VARIANTS The c.631G>A pathogenic mutation (also known as p.V211I), located in coding exon 6 of the BRCA2 gene, results from a G to A substitution at nucleotide position 631. The amino acid change results in valine to isoleucine at codon 211, an amino acid with highly similar properties; however, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. The c.7008-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides before coding exon 13 in the BRCA2 gene. The c.631G>A and c.7008-2A>T alterations have been identified in cis in multiple individuals and families with HBOC (Gaildrat PJ et al. Med. Genet. 2012 Oct;49(10):609-17; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4). These alterations have also been identified in cis in one individual with pancreatic adenocarcinoma (Lowery MA et al. Oncologist 2011;16(10):1397-402). Functional studies have demonstrated that the c.631G>A alteration leads to the skipping of coding exon 6, leading to a frameshift and alternate stop in coding exon 8 (Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4). Functional studies have also demonstrated that the c.7008-2A>T alteration leads to multiple transcripts of different lengths, most of which lead to a frameshift and alternate stop codon (Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4; Houdayer C et al. Hum. Mutat. 2012 Aug;33(8):1228-38; Colombo M et al. PLoS ONE 2013;8(2):e57173). Of note, c.631G>A and c.7008-2A>T are also designated as 859G>A and IVS13-2A>T, respectively, in published literature. Based on the available evidence, c.631G>A and c.7008-2A>T are classified as a pathogenic haplotype.
GeneDx RCV000235662 SCV000293482 pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7008-2A>T or IVS13-2A>T and consists of an A>T nucleotide substitution at the -2 position of intron 13 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 7236-2A>T. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been published, in both RT-PCR analyses of RNA and a PAXgene assay, to result in aberrant splicing (Pensabene 2009, Colombo 2009, Colombo 2013, Houdayer 2012). Based on the current evidence, we consider this variant to be pathogenic. BRCA2 c.631G>A and BRCA2 c.7008-2A>T have been published to co-occur in several probands with histories of breast, ovarian, and/or pancreatic cancer, absent of Fanconi Anemia, and are likely in cis (Pensabene 2009, Colombo 2009, Lowery 2011, Gaildrat 2012). Both of these variants are predicted to cause aberrant splicing and result in an out of frame deletion of an exon and either premature protein truncation or nonsense-mediated mRNA decay. Therefore, this allele, which likely carries both variants in cis is considered pathogenic. Of note, as these two variants are likely in cis, we would not expected this individual to have Fanconi Anemia.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113689 SCV000327577 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000113689 SCV000677696 likely pathogenic Breast-ovarian cancer, familial 2 2016-12-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000220759 SCV000683841 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-26 criteria provided, single submitter clinical testing This variant is predicted to abolish intron 13 splice acceptor site of the BRCA2 gene. RNA studies using patient-derived cells have shown that this variant causes skipping of exon 14 and premature truncation but does not completely abolish normal transcription (thus referred to as a “leaky” splice variant) (PMID: 19179552, 19423647). In mini-gene assays, this variant resulted in the production of multiple different aberrant transcripts and no detectable normal transcript (PMID: 23451180, 31191615). This variant has been reported in an individual affected with ductal carcinoma in situ (PMID: 30014164). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. This variant has been reported to co-occur with a pathogenic splice variant c.631G>A in the BRCA2 gene in seven unrelated European individuals affected with breast/ovarian cancer (PMID: 12960223, 19179552, 19423647, 23451180, 27125725) and in an individual affected with pancreatic adenocarcinoma (PMID: 21934105). In six of the individuals affected with breast/ovarian cancer, these variants were confirmed to occur on the same chromosome (in cis phase) by retro-transcription analysis or segregation analysis in family studies (PMID: 19179552, 19423647, 22962691). For several individuals who carried both variants (PMID: 21934105 and 5 individuals tested at Color), the phase of the two variants has not been determined. These two variants have not been reported in trans in the literature. Although this test cannot distinguish if c.631G>A and c.7008-2A>T variants occur in cis or in trans, these variants are likely to be in cis if found together in an individual. Medical management should be considered based on the patient's personal and family history.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000504523 SCV000695025 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7008-2A>T variant is located at a conserved position, known to affect splicing, with 5/5 splice prediction tools predicting a significant impact on splicing, which is further supported by multiple functional studies. A functional study, Colombo_2009, indicates the variant tocause a "leaky" effect on splicing, allowing the expression from the mutant allele of a transcript lacking both exons 7 and 14 (delta7, delta14) and a transcript lacking exon 7 only (delta7). The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP). Multiple publications cite the variant in affected individuals, predominantly, to co-occur with another pathogenic BRCA2 variant, c.631G>A. However, it remains unclear whether these variants were consistently observed in cis or trans. Multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic.
Invitae RCV000504523 SCV001587424 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-23 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 13 of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with a personal or family history of breast cancer (PMID: 19179552, 19423647, 22962691), and an individual with suspected Lynch syndrome (PMID: 25980754). In some cases, this variant occurred on the same chromosome as the c.631G>A (p.Val211Ile) variant in multiple family members (PMID: 19423647, 19179552). This variant is also known as IVS13-2A>T in the literature. ClinVar contains an entry for this variant (Variation ID: 52246). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 19179552, 23451180, 22505045). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113689 SCV000146998 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000113689 SCV000592089 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The c.7008-2A>T variant has been previously reported in the literature in 8/64 proband chromosomes of individuals of Italian descent with hereditary breast and/or ovarian cancer. However, no control chromosomes were evaluated to establish the prevalence of the variant in the general population (Colombo 2009, Pensabene 2009, Lowery 2011, Gaildrat 2012, Diez 2009). Interestingly, the authors of the above studies reported that this particular mutation was found to co-exist with another BRCA2 variant, c.631G>A, a co-occurrence that we have also observed in this individual. The c.7008-2A>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the -2 position of the splice consensus sequence. Indeed, functional studies have shown that the variant altered the natural splice sites leading to exon skipping due to modification of the 5' splice site (Pensabene 2009, Gaildrat 2012). In-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in all 5 programs. The variant has been reported twice in the UMD database as causal, and six times in the BIC database as clinically significant. However, as one of the studies pointed out, the c.7008-2A>T mutation may not contribute to cancer risk in the context of the c.631G>A variant, since it lies downstream of the other mutation identified in this individual that completely abolishes the synthesis of a functional gene product (Colombo 2009). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735596 SCV000863734 pathogenic Breast and/or ovarian cancer no assertion criteria provided clinical testing

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