ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9699_9702del (rs80359775)

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Total submissions: 21
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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 2020-10-21 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 clinical features of Fanconi anemia (Invitae). This finding is consistent with autosomal recessive inheritance and suggests that this variant contributes to disease. However, in two reported families, this variant occurred with a second pathogenic variant in individuals with early-onset breast cancer; both variants were also found in their healthy siblings, whose only features were abnormal cellular studies (PMID: 25639900). While this variant has been observed in individuals with breast, ovarian, pancreatic and brain cancer (PMID: 29161300, 29084914, 30716324, 29753700, Invitae), published data has shown inconsistent segregation with HBOC-associated cancers (PMID: 25639900). This suggests that this pathogenic variant may exhibit lower penetrance or an atypical clinical presentation (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
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 Medical Genetics, Oslo University Hospital RCV000031843 SCV000605701 likely pathogenic Breast-ovarian cancer, familial 2 2017-01-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000200978 SCV000695262 uncertain significance not specified 2020-10-28 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 and cited in HBOC patients. 2/4 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 frameshift. 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 6.4e-05 in 250272 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (6.4e-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 (example, Castera_2014, Rosenthal_2015, Kan_2015, Alemar_2017, Bunnell_2017, Rebbeck_2018, Palmero_2018, Delgado-Balderas_2018, Heramb_2018, Le Page_2019, Turner_2019), medulloblastoma (Waszak_2018) and intraductal papillary mucinous neoplasms (Skaro_2019). At-least one patient carried this variant along with a second BRCA2 variant (c.8878C>T, p.Gln2960X) and no associated phenotype of Fanconi Anemia (Alemar_2017). In our evaluation of this supporting literature, we conservatively ascertained at-least 11 transmissions of the variant allele and 4 transmissions of the reference allele to affected individuals in families with this variant. The ascertained penetrance of Hereditary Breast and Ovarian Cancer (0.44) due to this variant appears to be lower than expected allowing no firm conclusions 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 breast cancer 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." Multiple co-occurrences with other pathogenic variants have been reported from databases 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*, Le Page_2019-BRCA1 c.3759_3760del, p.Lys1254fs). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters including one expert panel (ENIGMA, classification dated 2016) have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The classifications are conflicting with pathogenic (n=6 to include the expert panel), likely pathogenic (n=1), and VUS (n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. A follow-up with the expert panel regarding an updated classification (ENIGMA) is pending at the time of this re-evaluation. Based on equivocal evidence of co-segregation with disease, presence with co-occurring BRCA2 variants in patients with and without features of Fanconi Anemia, and absence of concrete functional evidence as outlined above, the variant retained its classification as a VUS-possibly pathogenic risk variant.
PreventionGenetics,PreventionGenetics RCV000590308 SCV000805800 uncertain significance not provided 2016-02-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771139 SCV000902932 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-15 criteria provided, single submitter clinical testing This variant (c.9699_9702del, p.Cys3233Trpfs*15) deletes 4 nucleotides in exon 27 of the BRCA2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is also known as 9927del4 and c.9697_9700del in the literature. The mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein lacking the C-terminal RAD51 interaction domain (a.a. 3264-3330) and nuclear localization signals (a.a. 3263-3385). A different truncation variant (p.Tyr3308*) downstream of this variant is known to be pathogenic (ClinVar variation ID: 52916), indicating that variants that disrupt the C-terminal functional domains can cause disease. This variant has been reported in over ten individuals affected with breast or ovarian cancer (PMID: 16683254, 24549055, 25639900, 25863477, 28637432, 28888541, 29084914, 29161300, 29339979, 29875428; Color data), and pancreatic cancer (PMID: 25479140). This variant, in trans from another pathogenic variant in the BRCA2 gene, has been reported in individuals showing clinical features of autosomal recessive Fanconi anemia (communication with an external laboratory, ClinVar SCV000073900.8). In addition, a different variant leading to a similar protein sequence change (c.9693delA, p.Leu3232Phefs*17) has been shown to reduce RNA and protein levels and identified in sisters with Fanconi anemia in trans from another pathogenic variant in the BRCA2 gene (PMID: 30207912). However, the BRCA2 c.9699_9702del variant has not shown a consistent segregation with breast/ovarian/pancreatic cancer in family studies (PMID: 25639900). Several affected carriers also had a pathogenic BRCA1 or BRCA2 variant (PMID: 25639900, 29161300; Color internal data). This variant has also been reported in siblings with biallelic variants showing no symptoms of Fanconi anemia (PMID: 25639900). In addition, this variant has been identified in 17/281678 chromosomes in the general population by the Genome Aggregation Database (gnomAD), including 13/35212 chromosomes of Latino ancestry. These findings suggest that this variant may show reduced penetrance compared to other BRCA2 pathogenic variants. Although additional studies are necessary to determine the role of this variant in disease conclusively, this variant is expected to disrupt BRCA2 protein function and is, therefore, classified as Likely Pathogenic with reduced penetrance. Medical management should be considered based on the individual's personal and family history.
Ambry Genetics RCV000771139 SCV001181012 pathogenic Hereditary cancer-predisposing syndrome 2019-10-26 criteria provided, single submitter clinical testing The c.9699_9702delTATG pathogenic mutation, located in coding exon 26 of the BRCA2 gene, results from a deletion of 4 nucleotides at positions 9699 to 9702, causing a translational frameshift with a predicted alternate stop codon at codon 3247 (p.C3233Wfs*15). This alteration has been reported in hereditary breast and/or ovarian cancer families (van der Hout AH et al. Hum. Mutat. 2006 Jul;27:654-66; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Alemar B et al. PLoS ONE. 2017 Nov;12:e0187630). In addition, this mutation has been identified in multiple families with Fanconi Anemia in a compound heterozygous state with different pathogenic BRCA2 variant s in multiple individual with features consistent with Fanconi Anemia (Ambry internal data; Personal communication). This mutation has also been reported in the literature in trans with other BRCA2 pathogenic mutations in multiple families presenting with atypical (unusually mild) Fanconi Anemia (Rosenthal ET et al. Clin. Genet. 2015 Dec;88:533-41). As further evidence for pathogenicity, this truncation occurs 5' to two nonsense mutations at Y3308* and E3309*, which have been shown to be deleterious in in vitro and in vivo functional assays utilizing mouse embryonic stem cells (Kouznetsov SG et al. Nat. Med. 2008 Aug;14:875-81). Of note, this alteration is also designated as c.9699_9702del and 9927del4 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262735 SCV001440712 likely pathogenic Familial cancer of breast 2019-01-01 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000590308 SCV001449958 pathogenic not provided 2019-03-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590308 SCV001470467 uncertain significance not provided 2019-12-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285540 SCV001471994 uncertain significance none provided 2020-06-24 criteria provided, single submitter clinical testing The BRCA2 c.9699_c.9702delTATG; p.Cys3233fs variant (rs80359775) has been described in individuals with breast cancer and individuals with a clinical diagnosis of hereditary breast and ovarian cancer (Bunnell 2017, Rebbeck 2018, van der Hout 2006). Truncations downstream of this position have been classified as pathogenic by our laboratory (c.96725dupA;p.Tyr3255fs, c.9924C>G; p.Tyr3308Ter) and cited in HBOC patients (Alsop 2012, Tea 2014, van der Hout 2006, Waddell 2008). However, the c.9699_9702delTATG; p.Cys3233fs variant has also been described in individuals who also carry an additional BRCA2 variant, without Fanconi anemia symptoms (Alemar 2017, Rosenthal 2015). The variant is present in the ClinVar database with discrepant classifications, but is classified as pathogenic by an expert panel (Variation ID: 38260). The variant is found in the Latino population with an allele frequency of 0.04% (14/35226 alleles) in the Genome Aggregation Database. This variant results in a premature termination codon in the last exon of the BRCA2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated BRCA2 protein. Due to conflicting information, the clinical significance of the c.9699_c.9702delTATG; p.Cys3233fs variant is uncertain at this time. References: Alemar B et al. Probands From Southern Brazil: Are International Testing Criteria Appropriate for This Specific Population? BRCA1 and BRCA2 Mutational Profile and Prevalence in Hereditary Breast and Ovarian Cancer (HBOC). PLoS One. 2017 Nov 21;12(11):e0187630. Alsop K et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012 30:2654-2663. Bunnell AE et al. The Clinical Utility of Next Generation Sequencing Results in a Community-Based Hereditary Cancer Risk Program. J Genet Couns. 2017 Feb;26(1):105-112. Rebbeck TR et al. Mutational Spectrum in a Worldwide Study of 29,700 Families With BRCA1 or BRCA2 Mutations. Hum Mutat. 2018 May;39(5):593-620. Rosenthal ET et al. Exceptions to the Rule: Case Studies in the Prediction of Pathogenicity for Genetic Variants in Hereditary Cancer Genes. Clin Genet. 2015 Dec;88(6):533-41. Tea MK et al. Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. Maturitas. 2014 Jan;77(1):68-72. van der Hout AH et al. A DGGE System for Comprehensive Mutation Screening of BRCA1 and BRCA2: Application in a Dutch Cancer Clinic Setting. Hum Mutat. 2006 Jul;27(7):654-66.
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353983 SCV000592303 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing BRCA2, Exon 27, c.9699_9702delTATG, p.Cys3233TrpfsX15, Heterozygous, Uncertain Significance The BRCA2 p.Cys3233TrpfsX15 variant was identified in 1 of 862 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer (HBOC), and this study classifies this variant as deleterious (van der Hout 2006). The variant was also identified in dbSNP (ID: rs80359775) “With pathogenic allele”, Clinvitae database, ARUP Laboratories BRCA Mutations Database (as definitely pathogenic), the ClinVar database with conflicting classifications (pathogenic by Ambry Genetics and BIC, likely pathogenic by Counsyl and SCRP, and uncertain significance by GeneDX), and the BIC database (3X with clinical importance). In UMD the variant was classified as a causal variant, but it was also identified with a co-occurring pathogenic BRCA1 variant (p.Gln1327X), increasing the likelihood that the p.Cys3233TrpfsX15 variant does not have clinical significance. This variant was also identified in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 9 of 11534 chromosomes (frequency: 0.00078) from a population of Latino individuals, as well as at a much lower frequency in European (Non-Finnish) individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. Myriad published a case study on the pathogenicity of this variant (Rosenthal 2015). Although this variant is near the 3′ end of the BRCA2 gene, there are known pathogenic variants downstream of this position, i.e. c.9924C>G (p.Tyr3308X), therefore this variant is expected to cause HBOC and would typically be classified as pathogenic. However, the Myriad study reports observations of the variant in trans with other deleterious BRCA2 variants in two sets of patients with no reported symptoms of Fanconi Anemia, and in two more individuals who also carry a pathogenic variant in BRCA2. The study further reports that they have detected this variant in 67 apparently unrelated individuals undergoing comprehensive analysis of BRCA1 and BRCA2. These observations currently meet the threshold for a benign designation. The study further states that family testing outcomes do not demonstrate consistent segregation of the variant with breast or ovarian cancer, although some contribution of the variant to the familial aggregation of cancer cannot be excluded. Therefore the Myriad study states that BRCA2 c.9699_9702del is currently reported as a ‘special interpretation variant’. The authors state that there is as yet no compelling hypothetical mechanism as to why BRCA2 c.9699_9702del is not causative of HBOC. They further conclude that it is important to note that the variant is not yet proven to have absolutely no impact on cancer risk, although the available data suggests that the risk falls far short of what is considered to be diagnostic of the associated clinical syndrome. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of Uncertain significance.
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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