ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9699_9702del (p.Cys3233fs) (rs80359775)

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Total submissions: 17
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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) RCV000031843 SCV000301412 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000168365 SCV000073900 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-09 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BRCA2 gene (p.Cys3233Trpfs*15). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 186 amino acids of the BRCA2 protein. This variant is present in population databases (rs781465150, ExAC 0.08%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in individuals with features of a mild form of Fanconi anemia (PMID: 25639900, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. However, family testing has not shown consistent segregation of this variant with breast and/or ovarian cancer, resulting in it being classified as a "special interpretation" variant for autosomal dominant hereditary breast and ovarian cancer (PMID: 25639900). ClinVar contains an entry for this variant (Variation ID: 38260). This variant disrupts the C-terminus of the BRCA2 protein. Other variants that disrupt this region (p.Gln3299Ilefs*29 and p.Tyr3308*) have been determined to be pathogenic (PMID: 17026620, 22711857, 18593900, 18607349, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131044 SCV000185974 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
GeneDx RCV000590308 SCV000210802 uncertain significance not provided 2019-01-09 criteria provided, single submitter clinical testing This deletion of four nucleotides is denoted BRCA2 c.9699_9702delTATG at the cDNA level and p.Cys3233TrpfsX15 (C3233WfsX15) at the protein level. Using alternate nomenclature, this variant would be defined as 9927_9930delTATG or 9927del4. The normal sequence, with the bases that are deleted in brackets, is TTTG[delTATG]GCCA. The deletion causes a frameshift, which changes a Cysteine to a Tryptophan at codon 3233, and creates a premature stop codon at position 15 of the new reading frame. This variant has been observed in individuals with a personal and/or family history of breast and/or ovarian cancer, and in an individual with breast cancer who also carried a second BRCA2 frameshift variant (van der Hout 2006, Castera 2014, Kang 2015, Alemar 2017, Bunnell 2017, Grindedal 2017). BRCA2 c.9699_9702delTATG is predicted to result in a truncated protein that removes the nuclear localization signals, the Cyclin A binding domain, and part of the RAD51 binding domain (Esashi 2005, Borg 2010, Roy 2012). Although frameshift variants are typically considered pathogenic, this variant occurs just upstream of a well-known polymorphism that also results in a premature stop of translation (Lys3326Ter). In addition, this variant has been seen in trans with a known pathogenic BRCA2 variant in several individuals without classic features of Fanconi anemia and was not found to consistently segregate with cancer in other families harboring this variant (Rosenthal 2015). Despite the seemingly damaging nature of this variant and some evidence of pathogenicity, based on currently available and internal data, we consider this to be a variant of uncertain significance.
Counsyl RCV000031843 SCV000220562 likely pathogenic Breast-ovarian cancer, familial 2 2014-07-29 criteria provided, single submitter literature only
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031843 SCV000328164 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000031843 SCV000575748 pathogenic Breast-ovarian cancer, familial 2 2016-01-13 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000200978 SCV000592303 uncertain significance not specified criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000031843 SCV000605701 likely pathogenic Breast-ovarian cancer, familial 2 2017-01-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000200978 SCV000695262 uncertain significance not specified 2019-04-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9699_9702delTATG (p.Cys3233TrpfsX15) results in a premature termination codon located in the BRCA2 C-terminal domain encoded by exon 27 that contains a nuclear localization signal, interacts with RAD51 in a CDK-dependent manner, and is required for maintaining genomic stability after DNA damage. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.9770_9773delAAGA, p.Lys3257fsX17; c.9924C>G, p.Tyr3308X) and cited in HBOC patients. 3/5 splicing prediction tools predict that this variant may strengthen a cryptic 3' splicing acceptor site, which may lead to alternative start of exon 27 and frameshit. However, these predictions have yet to be confirmed by functional studies. This variant was predicted not to result in Nonsense-Mediated Decay and associated with stable mutant proteins (Rebbeck_2018). The variant allele was found at a frequency of 6e-05 in 281678 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (6e-05 vs 0.00075), allowing no conclusion about variant significance. The variant, c.9699_9702delTATG, has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Castera_2014, Rosenthal_2015, Kan_2015, Alemar_2017, Bunnell_2017, Rebbeck_2018). In our evaluation of this supporting literature, we conservatively ascertained at-least 10 transmissions of the variant allele and 3 transmissions of the reference allele to affected individuals In families with this variant. Since the ascertained penetrance of Hereditary Breast and Ovarian Cancer (0.42) due to this variant appears to be lower than expected (estimated at 0.5), no conclusions can be drawn from these data. Rosenthal_2015 evaluated the variant of interest and observed the variant in at least 1 Family with a suggested mild form of Fanconi Anemia. This family was ascertained because a female was diagnosed with BrC at 22 y/o and carried the variant of interest and another BRCA2 variant, c.145G>T (p.Glu49X) believed to be in trans, although not confirmed. Her brother (15 y/o) who carried the same two variants (identical genotype) was indicated to have no symptoms at the time of publication. However, both siblings were reported to have had abnormal chromosome mitomycin C stress testing. The authors went on to state that they "detected this variant in 67 apparently unrelated individuals undergoing comprehensive analysis of BRCA1 and BRCA2, it has been seen in two individuals who also carry a pathogenic variant in BRCA1." The authors further evaluated the variant of interest in the Myriad database and found multiple relatives of probands that carried the variant of interest that were either affected or unaffected, along with affected individuals that did not carry the variant of interest. Therefore, the authors concluded that the variant of interest needs to be reported as a "special interpretation variant" and conclude "there is as yet no compelling hypothetical mechanism as to why BRCA2 c.9699_9702del is not causative of HBOC. It is important to note that the variant of interest described here is yet proven to have absolutely no impact on cancer risk, although the available data in each case suggest that the risk falls far short of what is considered to be diagnostic of the associated clinical syndrome. Co-occurrences with other pathogenic variants have been reported from database and publications (Rosenthal_2015, Alemar_2017), providing supporting evidence for a benign role (UMD-BRCA1 c.3979C>T, p.Gln1327X; BIC-BRCA1 c.3759_3760delTA, p.Lys1254fsX12; Alemar_2017-BRCA2 c.8878C>T, p.Gln2960X; Rosenthal_2015-BRCA2 c.145G>T , p.Glu49*). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The classifications are conflicting with pathogenic (n=3 to include the expert panel), likely pathogenic (n=1), and VUS (n=3). Based on the evidence outlined above, the variant was classified as a VUS-possibly pathogenic.
PreventionGenetics,PreventionGenetics RCV000590308 SCV000805800 uncertain significance not provided 2016-02-01 criteria provided, single submitter clinical testing
Color RCV000771139 SCV000902932 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000771139 SCV001181012 pathogenic Hereditary cancer-predisposing syndrome 2019-10-26 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other acmg-defined mutation (i.e. initiation codon or gross deletion);Other strong data supporting pathogenic classification
Sharing Clinical Reports Project (SCRP) RCV000031843 SCV000054451 likely pathogenic Breast-ovarian cancer, familial 2 2012-07-30 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031843 SCV000147700 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000168365 SCV000588014 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Center for Reproductive Medicine,Shandong Provincial Hospital Affiliated to Shandong University RCV000770914 SCV000902413 pathogenic Genetic non-acquired premature ovarian failure 2018-10-01 no assertion criteria provided literature only

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