Submissions for variant NM_000059.4(BRCA2):c.5199C>T (p.Ser1733=)

gnomAD frequency: 0.00488  dbSNP: rs28897734

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113396	SCV000577985	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.0109 (Finnish), derived from ExAC (2014-12-17).
Invitae	RCV000044603	SCV000072616	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000113396	SCV000154097	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-04-04	criteria provided, single submitter	literature only
GeneDx	RCV000152876	SCV000167371	benign	not specified	2013-10-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113396	SCV000195989	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000152876	SCV000202288	benign	not specified	2016-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162368	SCV000212676	likely benign	Hereditary cancer-predisposing syndrome	2014-05-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768598	SCV000219348	benign	Breast and/or ovarian cancer	2016-11-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113396	SCV000383708	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-20	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000277308	SCV000383709	likely benign	Fanconi anemia complementation group D1	2018-03-20	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044603	SCV000494329	benign	Hereditary breast ovarian cancer syndrome	2014-01-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000475668	SCV000541048	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000488323	SCV000574953	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BP7, BS2
Fulgent Genetics, Fulgent Genetics	RCV002477147	SCV000575739	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-05-17	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000152876	SCV000586958	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000152876	SCV000588098	benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000488323	SCV000602774	benign	not provided	2023-11-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152876	SCV000605772	benign	not specified	2016-05-23	criteria provided, single submitter	clinical testing	p.Ser1733Ser in exon 11 of BRCA2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 1.09% (72/6606) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs28897734).
Color Diagnostics, LLC DBA Color Health	RCV000162368	SCV000683686	benign	Hereditary cancer-predisposing syndrome	2015-04-06	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113396	SCV000743304	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-10	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113396	SCV000744464	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000152876	SCV000805718	benign	not specified	2017-02-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000488323	SCV002010360	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000044603	SCV002026110	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162368	SCV002533929	benign	Hereditary cancer-predisposing syndrome	2020-01-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000152876	SCV002550346	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113396	SCV000146562	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2000-06-12	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113396	SCV000189308	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000152876	SCV000591950	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 p.Ser1733Ser variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site; in addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified in 76 of 12892 proband chromosomes (frequency: 0.006) from individuals or families with breast or ovarian cancer, or pancreatic carcinoma/melanoma-prone families (Balabas 2010, Bartsch 2009, Borg 2010, Schroeder 2010, Slater 2010, Stegel 2011, van der Hout 2006, Wagner 1999, Weber 2006, Yang 2009). The variant was also present in 5 of 310 control chromosomes (frequency: 0.016) from healthy individuals (Cvok 2008, Stegel 2011). The variant was identified in dbSNP (ID: rs28897734) with a minor allele frequency of 0.0016 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, Clinvitae database, Fanconi Anemia Mutation Database (LOVD), COSMIC, the ClinVar database (classified as “benign” by six submitters and “likely benign” by two submitters), GeneInsight COGR database (submitted by three clinical laboratories, with classifications of benign, presumed benign, and unclassified), the BIC database (11X with no clinical importance), and the BRCA Share (UMD) database (95X with a neutral classification). In the BRCA Share database, 15 samples were listed with co-occurring pathogenic BRCA1 or BRCA2 variants, increasing the likelihood that the p.Ser1733Ser variant is not clinically significant. The variant was identified at polymorphic allelic frequencies in two HAPMAP populations listed in the variant’s dbSNP record: HAPMAP-TSI (Toscans in Italy) and HAPMAP-MEX (Mexican ancestry in Los Angeles). The variant is also found at a polymorphic frequency (72/6606 alleles, frequency 0.0109) in a population of European (Finnish) individuals identified in the Exome Aggregation Consortium (ExAC) database; one of these individuals was homozygous for the variant, and two individuals from a cohort of European (Non-Finnish) were also homozygotes, increasing the likelihood of this being a benign variant. In addition, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000113396	SCV000733262	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000488323	SCV000778682	benign	not provided	2017-05-15	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162368	SCV000787935	likely benign	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000152876	SCV001799242	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000152876	SCV001906249	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000152876	SCV001954614	benign	not specified		no assertion criteria provided	clinical testing