Submissions for variant NM_000059.4(BRCA2):c.2830A>T (p.Lys944Ter)

gnomAD frequency: 0.00001  dbSNP: rs80358533

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077287	SCV000300563	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	RCV000131101	SCV000186031	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-01	criteria provided, single submitter	clinical testing	The p.K944* pathogenic mutation (also known as c.2830A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 2830. This changes the amino acid from a lysine to a stop codon within coding exon 10. This mutation has been detected in multiple breast and ovarian cancer families to date (Mote PA et al. Genes Chromosomes Cancer, 2004 Mar;39:236-48; Capalbo C et al. Ann Oncol, 2006 Jun;17 Suppl 7:vii34-40; Thomassen M et al. Acta Oncol, 2008;47:772-7; Bodd TL et al. Acta Paediatr., 2010 Nov;99:1741-3; Heidemann S et al. Breast Cancer Res Treat, 2012 Aug;134:1229-39; Vietri MT et al. Clin. Chem. Lab. Med., 2013 Dec;51:2319-24; Lucas AL et al. Cancer, 2014 Jul;120:1960-7; Rebbeck TR et al. Breast Cancer Res, 2016 11;18:112; Susswein LR et al. Genet Med, 2016 08;18:823-32; Weren RD et al. Hum. Mutat., 2017 02;38:226-235; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Wen WX et al. J Med Genet, 2018 02;55:97-103; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Chen B et al. Aging (Albany NY), 2020 02;12:3140-3155; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In one study, this variant was reported in 2/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in patients with pancreatic cancer (Lowery MA et al. J Natl Cancer Inst, 2018 10;110:1067-1074; Sorscher S et al. Oncologist, 2021 Jul). Of note, this alteration is also designated as 3058A>T in the 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	RCV000212222	SCV000210293	pathogenic	not provided	2021-01-06	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; Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25525159, 26659639, 20104584, 23683081, 26064523, 25428789, 9150154, 16760289, 23940062, 22535016, 11430722, 20608899, 10359546, 16847550, 14732925, 24737347, 9892109, 18465347, 11710835, 27767231, 27836010, 28127413, 26681312, 29339979, 28993434, 29506128, 29446198, 30720243, 30702160, 30322717, 31589614, 32885271, 33087929, 33287145)
Color Diagnostics, LLC DBA Color Health	RCV000131101	SCV000292148	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-20	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 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 individuals with a personal and/or family history of breast, ovarian, or pancreatic cancer (PMID: 18465347, 18284688, 19574032, 20104584, 22535016, 23096105, 23683081, 29446198, 30322717, 32885271, 34072659. 34309133). This variant has been identified in 3/282020 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212222	SCV000296716	pathogenic	not provided	2019-11-26	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in a number of individuals with breast and ovarian cancers (PMID: 27767231 (2017), 26681312 (2015), 23940062 (2013), 23683081 (2013), 20104584 (2010), 16760289 (2006), 9150154 (1997)) and in one case of pancreatic cancer (PMID: 29506128 (2018)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077287	SCV000326771	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000044070	SCV000540994	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000077287	SCV000605671	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000077287	SCV000677672	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496649	SCV000694634	pathogenic	Hereditary breast ovarian cancer syndrome	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2830A>T (p.Lys944X) 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 250612 control chromosomes. c.2830A>T 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 and one expert panel (ENIGMA) 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077287	SCV000744431	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000496649	SCV000838779	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000212222	SCV001450006	pathogenic	not provided	2017-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV000496649	SCV001588423	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys944*) 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 (rs80358533, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150154, 20104584, 23683081, 26681312, 27836010). This variant is also known as 3058A>T. ClinVar contains an entry for this variant (Variation ID: 51355). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000212222	SCV002021563	pathogenic	not provided	2022-09-30	criteria provided, single submitter	clinical testing
Research Institute, Aichi Cancer Center	RCV000496649	SCV002503891	pathogenic	Hereditary breast ovarian cancer syndrome	2022-02-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131101	SCV002535532	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212222	SCV002550312	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077287	SCV000109084	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2006-11-27	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077287	SCV000146122	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496649	SCV000587645	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077287	SCV000733241	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785217	SCV000923785	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV001028039	SCV001190805	pathogenic	Fanconi anemia complementation group D1	2020-02-05	no assertion criteria provided	clinical testing
New York Genome Center	RCV000077287	SCV001431059	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-10	no assertion criteria provided	clinical testing	The c.2830A>T (p.Lys944Ter) variant identified in the BRCA2 gene of this individual leads to the premature termination of the protein at amino acid 944/3419 (coding exon 11/27). This variant is found with low frequency in gnomAD (3 heterozygotes, 0 homozygotes, allele frequency: 1.06e-5) suggesting it is not a common benign variant in the populations represented in these databases. This variant is reported as Pathogenic in ClinVar (VarID:51355) after review by the Expert Panel and has been reported in many affected individuals in the literature [PMID: 24737347; PMID: 23683081; PMID: 20104584; PMID: 28346442]. It is reported here as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358552	SCV001554320	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Lys944X variant was identified in 8 of 25752 proband chromosomes (frequency: 0.0003) from individuals or families with breast and ovarian cancer (Blay 2013, Borg 2010, Capalbo 2006, Hakansson 1997, Heramb 2018, Susswein 2015). The variant was also identified in the following databases: dbSNP (ID: rs80358533) as "With Pathogenic allele", ClinVar (12x pathogenic), Clinvitae (5x pathogenic), GeneInsight-COGR (2x pathogenic), Cosmic (1x, confirmed somatic, in carcinoma of the biliary tract), LOVD 3.0 (11x), UMD-LSDB (8x causal), BIC Database (6x pathogenic), and ARUP Laboratories (pathogenic). The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 3 of 276604 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 23994 chromosomes (freq: 0.00004), European in 1 of 126388 chromosomes (freq: 0.000008), and South Asian in 1 of 30678 chromosomes (freq: 0.00003). The variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The c.2830A>T variant leads to a premature stop codon at position 944 which is predicted to lead to 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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212222	SCV001954387	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077287	SCV004243595	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing