Submissions for variant NM_000059.4(BRCA2):c.9038C>T (p.Thr3013Ile)

gnomAD frequency: 0.00022  dbSNP: rs28897755

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)	RCV000031788	SCV001161623	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 1.80E-06
Invitae	RCV000045695	SCV000073708	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131061	SCV000185991	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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	RCV000768639	SCV000219417	likely benign	Breast and/or ovarian cancer	2020-02-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000031788	SCV000220479	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-03	criteria provided, single submitter	literature only
Illumina Laboratory Services, Illumina	RCV000347597	SCV000383799	likely benign	Fanconi anemia complementation group D1	2017-04-28	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	RCV000045695	SCV000383800	likely benign	Hereditary breast ovarian cancer syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454455	SCV000538499	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 8 B/LB
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034471	SCV000609923	likely benign	not provided	2017-06-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131061	SCV000684018	likely benign	Hereditary cancer-predisposing syndrome	2015-03-09	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031788	SCV000743357	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031788	SCV000744553	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-31	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131061	SCV000803164	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000454455	SCV000805791	benign	not specified	2017-11-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034471	SCV000883501	likely benign	not provided	2018-02-02	criteria provided, single submitter	clinical testing	The BRCA2 c.9038C>T; p.Thr3013Ile variant (rs28897755) has been reported in the literature in individuals with a personal or family history of hereditary breast and ovarian cancer (Houdayer 2012, Malone 2000, Sanz 2010). However, this variant has also been found incidentally in an individual with no personal or family history of cancer (Johnston 2012). This variant is reported with conflicting interpretations of pathogenicity in ClinVar, with most sources classifying as benign or likely benign (Variation ID: 38205) and is seen in the general population at an overall frequency of 0.02% (65/276280 alleles, including 1 homozygote) in the Genome Aggregation Database. The threonine at codon 3013 is moderately conserved but computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to have no impact on protein function. In agreement with this, functional analysis of this variant protein shows no defects in DNA double-strand break repair using a cell-based homology directed repair assay (Guidugli 2013). Based on the above information, this variant is considered likely benign. REFERENCES Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology directed repair activity. Cancer Res. 2013 Jan 1; 73(1): 265–275. Houdayer C et al. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat. 2012 Aug;33(8):1228-38. Johnston J et al. Secondary Variants in Individuals Undergoing Exome Sequencing: Screening of 572 Individuals Identifies High-Penetrance Mutations in Cancer-Susceptibility Genes. Am J Hum Genet. 2012 Jul 13; 91(1): 97–108. Malone K et al. Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer. 2000 Mar 15;88(6):1393-402. Sanz D et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010 Mar 15;16(6):1957-67.
Mendelics	RCV000031788	SCV001139243	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034471	SCV001249498	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS3:Supporting
Genetic Services Laboratory, University of Chicago	RCV000454455	SCV002069337	uncertain significance	not specified	2018-07-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131061	SCV002531999	likely benign	Hereditary cancer-predisposing syndrome	2021-02-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000454455	SCV002551841	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272035	SCV002556674	benign	Familial cancer of breast	2021-08-02	criteria provided, single submitter	clinical testing	The BRCA2 c.9038C>T variant is classified as Benign (BS1, BS3, BP4, BP6)
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034471	SCV000043237	probably not pathogenic	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Likely benign.
Sharing Clinical Reports Project (SCRP)	RCV000031788	SCV000054396	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2006-03-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031788	SCV000147519	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148415	SCV000190114	likely benign	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000454455	SCV000592250	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 p.Thr3013Ile variant was identified in 5 of 2946 proband chromosomes (frequency: 0.002) from individuals with breast or ovarian cancer (Claes 2004, Diez 2003, Kim 2005). This variant was listed in dbSNP (ID: rs28897755) “With probable-non-pathogenic allele”, and in the Exome Variant Server ESP project with a frequency of 0.0004. It was identified in several populations from the HapMap project, including: HAPMAP-MEX (frequency: 0.03), HapMap-JPT (frequency: 0.012), and HapMap-HCB (frequency: 0.012), increasing the likelihood that this is a low frequency benign variant in certain populations of origin. The variant was also identified in the following databases: HGMD, LOVD, BIC (53X with no clinical importance), and UMD (13X as a neutral variant). In UMD it was twice reported to co-occur with pathogenic mutations in the BRCA1 or BRCA2 genes (BRCA2 c.1257delT (p.Cys419TrpfsX11), BRCA1 c.5266dup (p.Gln1756ProfsX74)), increasing the likelihood that this variant does not have clinical significance. In addition, in silico studies and functional studies predict this that this variant has a neutral effect on BRCA2 protein function (Guidugli 2013, Karachin 2008). The p.Thr3013 residue is not conserved in mammals and lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein but this information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
True Health Diagnostics	RCV000131061	SCV000787959	likely benign	Hereditary cancer-predisposing syndrome	2017-09-07	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000454455	SCV001954503	benign	not specified		no assertion criteria provided	clinical testing