Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Evidence- |
RCV000031392 | SCV000300576 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2016-09-08 | reviewed by expert panel | curation | Variant allele predicted to encode a truncated non-functional protein. |
Ambry Genetics | RCV000131097 | SCV000186027 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-13 | criteria provided, single submitter | clinical testing | The c.2957_2958insG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from an insertion of one nucleotide at position 2957, causing a translational frameshift with a predicted alternate stop codon (p.N986Kfs*2). This mutation was previously identified in one individual with pancreatic ductal adenocarcinoma (Golan T et al. Br. J. Cancer. 2014 Sep; 111(6):1132-8; Holter S et al. J. Clin. Oncol. 2015 Oct; 33(28):3124-9) and in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
Consortium of Investigators of Modifiers of BRCA1/2 |
RCV000031392 | SCV000326790 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2015-10-02 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000463291 | SCV000549846 | pathogenic | Hereditary breast ovarian cancer syndrome | 2023-07-06 | criteria provided, single submitter | clinical testing | This premature translational stop signal has been observed in individual(s) with breast and pancreatic cancer (PMID: 25940717, 26219728). For these reasons, this variant has been classified as Pathogenic. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 37811). This variant is present in population databases (rs80359365, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Asn986Lysfs*2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). |
Gene |
RCV000482218 | SCV000569916 | pathogenic | not provided | 2024-12-10 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3185_3186insG; This variant is associated with the following publications: (PMID: 25940717, 23929434, 30720243, 31892343, 25072261, 16683254, 25583207, 29446198, 32427313, 32885271, 30130155, 29922827) |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000482218 | SCV000600536 | pathogenic | not provided | 2023-02-06 | criteria provided, single submitter | clinical testing | This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/249782 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32885271 (2021), 32427313 (2020), 30130155 (2018)) or pancreatic cancer (PMID: 25940717 (2015)). Based on the available information, this variant is classified as pathogenic. |
Counsyl | RCV000031392 | SCV000677674 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2017-05-09 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000131097 | SCV000688780 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-03-02 | criteria provided, single submitter | clinical testing | This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 1 individual affected with both breast and pancreatic cancer (PMID: 25072261, 25940717) and has been identified in 4 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/249782 chromosomes 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000463291 | SCV000694655 | pathogenic | Hereditary breast ovarian cancer syndrome | 2020-09-21 | criteria provided, single submitter | clinical testing | Variant summary: BRCA2 c.2957_2958insG (p.Asn986LysfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 249782 control chromosomes. c.2957_2958insG has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Holter_2015, Golan_2014, Rebbeck_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
CHEO Genetics Diagnostic Laboratory, |
RCV001798040 | SCV002042611 | pathogenic | Breast and/or ovarian cancer | 2020-05-28 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000131097 | SCV002533749 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-02-10 | criteria provided, single submitter | curation | |
Baylor Genetics | RCV004566767 | SCV005059093 | pathogenic | Familial cancer of breast | 2024-01-23 | criteria provided, single submitter | clinical testing | |
Sharing Clinical Reports Project |
RCV000031392 | SCV000053997 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2011-03-24 | no assertion criteria provided | clinical testing | |
Breast Cancer Information Core |
RCV000031392 | SCV000146149 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2003-12-23 | no assertion criteria provided | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV001355425 | SCV001550307 | pathogenic | Malignant tumor of breast | no assertion criteria provided | clinical testing | The BRCA2 p.Asn986Lysfs*2 variant was identified in 1 of 612 proband chromosomes (frequency: 0.002) from individuals or families with pancreatic cancer (Holter 2015). The variant was also identified in dbSNP (ID: rs80359365) “With Pathogenic allele”, ClinVar (classified as pathogenic by ENIGMA expert panel, Invitae, GeneDx, Ambry Genetics, and 7 other submitters), LOVD 3.0 (2x classified as pathogenic), and UMD-LSDB (1x classified 5-causal). The variant was identified in control databases in 1 of 249782 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 1 of 15882 chromosomes (freq: 0.00006), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other, or South Asian populations. The c.2957_2958insG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 986 and leads to a premature stop codon at position 987. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. |