Submissions for variant NM_000059.4(BRCA2):c.7757G>A (p.Trp2586Ter)

gnomAD frequency: 0.00001  dbSNP: rs80359003

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077410	SCV000282448	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045302	SCV000073315	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp2586*) 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). This variant is present in population databases (rs80359003, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer and prostate cancer (PMID: 11802209, 12673801, 16528604, 23035815, 23569316, 23633455, 25485004). ClinVar contains an entry for this variant (Variation ID: 52401). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131087	SCV000186017	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-27	criteria provided, single submitter	clinical testing	The p.W2586* pathogenic mutation (also known as c.7757G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7757. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This alteration has been reported in multiple breast and/or ovarian cancer families (Perkowska M et al. Hum. Mutat., 2003 May;21:553-4; Jönsson G et al. Cancer Res., 2005 Sep;65:7612-21; Alsop K et al. J Clin Oncol, 2012 Jul;30:2654-63; Conner JR et al. Gynecol. Oncol., 2014 Feb;132:280-6; Walker R et al. Can Urol Assoc J, 2014 Nov;8:E783-8; Li JY et al. Int J Cancer, 2019 01;144:281-289; Petridis C et al. Cancer Epidemiol Biomarkers Prev, 2019 07;28:1162-1168; Lattimore V et al. Breast Cancer Res Treat, 2021 Feb;185:583-590; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in individuals diagnosed with prostate cancer (Willems-Jones A et al. BJU Int. 2012 Dec;110(11 Pt C):E1181-6; Sandhu SK et al. Ann Oncol, 2013 May;24:1416-8; Walker R et al. Can Urol Assoc J 2014 Nov; 8(11-12):E783-8). This mutation has been identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this alteration is also designated as 7985G>A 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 or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000215688	SCV000278876	pathogenic	not provided	2023-03-03	criteria provided, single submitter	clinical testing	Nonsense 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; Observed in individuals with personal or family history of BRCA2-related cancers (Perkowska et al., 2003; Jonsson et al., 2005; George et al., 2013; Walker et al., 2014; Murali et al., 2021; Evans et al., 2022); 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 7985G>A; This variant is associated with the following publications: (PMID: 25628955, 25371446, 26833046, 28127413, 11802209, 19620486, 34657373, 29922827, 28888541, 23633455, 12673801, 23035815, 24333842, 16140926, 16528604, 27225637, 25485004, 12442275, 22655046, 25716084, 23233716, 27836010, 19899408, 17761984, 22711857, 29752822, 29446198, 30720243, 25525159, 31825140, 30787465, 33087929, 23524863, 20104584, 23569316, 33113089, 34399810, 33471991, 33758026)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077410	SCV000327724	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131087	SCV000537635	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 16 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in several individuals affected with breast and/or ovarian cancer (PMID: 12673801, 22711857, 23633455, 24333842, 33113089, 33471991, Color internal data). This variant has been identified in families with suspected hereditary breast and ovarian cancer syndrome, including 21 families among the CIMBA participants (PMID: 11802209, 16528604, 29446198). This variant has been identified in 2/251434 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.
Department of Pathology and Molecular Medicine, Queen's University	RCV000045302	SCV000588116	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000215688	SCV000600767	pathogenic	not provided	2016-07-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045302	SCV000695098	pathogenic	Hereditary breast ovarian cancer syndrome	2021-05-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7757G>A (p.Trp2586X) 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 8e-06 in 251434 control chromosomes. c.7757G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a large consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000077410	SCV002761531	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-06-05	criteria provided, single submitter	clinical testing	The BRCA2 c.7757G>A variant is classified as Pathogenic (PVS1, PM2, PP5) The BRCA2 c.7757G>A variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 2586. The variant is rare in population databases (gnomAD allele frequency = 0.00081% (PM2). The variant has been reported in dbSNP (rs80359003) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 52401).
Baylor Genetics	RCV003460613	SCV004213716	pathogenic	Familial cancer of breast	2023-07-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000045302	SCV004848262	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Trp2586X variant in BRCA2 has been reported in at least 14 individuals with BRCA2-related cancer (Perkowska 2003, Willems-Jones 2012, George 2013, Li 2018, BIC database). It has also been identified in 2/113726 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant leads to a premature termination codon at position 2586, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Another variant, c.7758G>A, resulting in the same amino acid change has been identified in individuals with BRCA2-related cancers and is classified as pathogenic by this laboratory. Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 52401). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate, PS1.
Sharing Clinical Reports Project (SCRP)	RCV000077410	SCV000109208	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-04-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077410	SCV000147172	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045302	SCV000587905	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000077410	SCV000592139	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Trp2586X variant has been reported in 8/4826 proband chromosomes (frequency 0.002) of individuals with breast and/or ovarian cancer increasing the likelihood this variant is pathogenic, however, no normal population controls were included in these studies (Alsop 2012, Callahan 2007, Jonsson 2005, Meindl 2002, Perkowska 2003, Watson 2009, Weitzel 2005) It is reported in the BIC (x5) database as clinically significant. The variant leads to a premature stop codon at position 2586 which is predicted to cause premature truncation or an absent protein product and loss of function. Loss of function of the BRCA2 gene is an established disease mechanism for hereditary breast cancer. This variant is classified as pathogenic
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735604	SCV000863742	pathogenic	Breast and/or ovarian cancer	2015-07-13	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732622	SCV005355655	pathogenic	BRCA2-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The BRCA2 c.7757G>A variant is predicted to result in premature protein termination (p.Trp2586*). This variant was reported in individuals with breast cancer and/or ovarian cancer (Perkowska et al. 2003. PubMed ID: 12673801; Alsop et al. 2012. PubMed ID: 22711857; George et al. 2013. PubMed ID: 23633455; Conner et al. 2014. PubMed ID: 24333842; Supplemental Table 4, Li et al. 2018. PubMed ID: 29752822; Supplemental Table, Petridis et al. 2019. PubMed ID: 31263054) and in individuals with prostate cancer (Supplemental Table 2, Willems-Jones et al. 2012. PubMed ID: 23035815; Castro et al. 2013. PubMed ID: 23569316; Walker et al. 2014. PubMed ID: 25485004). This variant was also reported in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database (Supplemental Table 1, Rebbeck et al. 2018. PubMed ID: 29446198). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is reported as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/52401/). Loss of function variants in BRCA2 are known to be pathogenic. Taken together, this variant is interpreted as pathogenic.