Submissions for variant NM_000059.4(BRCA2):c.68-7T>A

gnomAD frequency: 0.00277  dbSNP: rs81002830

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077384	SCV000783127	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-12	reviewed by expert panel	curation	IARC class based on combined odds from multifactorial likelihood analysis, thresholds for class as per Easton et al. 2007 (PMID: 17924331). Class 1 Not Pathogenic based on posterior probability of pathogenicity = 7.44x10-115. There was no evidence for increased risk of breast cancer (OR 1.03; 95%CI 0.86-1.24) from case-control analysis of 83636 individuals. Nor for a deleterious effect of the variant when co-occurring with a pathogenic variant. Quantitative splicing analysis revealed an exon 3 exclusion rate of 13% in carriers compared to 3% in controls. Exon 3 exclusion from the variant allele is estimated at 20%.
Invitae	RCV000045051	SCV000073064	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000074550	SCV000108635	benign	Familial cancer of breast	2014-04-25	criteria provided, single submitter	clinical testing	The variant is found in BRCA1-BRCA2,ENDOM-HEREDIC,BR-OV-HEREDIC panel(s).
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077384	SCV000195944	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000077384	SCV000220412	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-06-13	criteria provided, single submitter	literature only
Pathway Genomics	RCV000077384	SCV000223767	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000168529	SCV000228764	likely benign	not specified	2014-10-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000077384	SCV000383601	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-27	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000362403	SCV000383602	likely benign	Fanconi anemia complementation group D1	2017-04-27	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	RCV000045051	SCV000494401	benign	Hereditary breast ovarian cancer syndrome	2016-08-23	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.68-7T>A variant involves the alteration of a non-conserved intronic nucleotide. 2/5 splice prediction tools predict a significant impact on normal splicing. Although functional studies evaluating the splicing effect of this variant show a production of a exon 3 deletion transcript wild type control DNA also showed the production of this exon 3 deletion transcript albeit at a lesser quantitative amount (Sanz_2010 and Muller_2010). Furthermore, an additional functional study evaluating the variant of interest's effect on key aspects of BRCA2 function such homologous recombination and sensitivity to DNA damaging agents showed comparable abilities to the wild-type BRCA2. This variant was found in 282/118368 control chromosomes at a frequency of 0.0023824, which is approximately 3.2 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this variant is likely a benign polymorphism. This variant has been reported in many HBOC patients/families. It has been shown not to cosegregate with disease in two families (Santos_2014). In addition, the variant has been reported to co-occur with multiple different deleterious variants in BRCA1/2 (UMD), strongly suggesting for a benign outcome. Most of the clinical diagnostic laboratories in ClinVar have classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168529	SCV000538468	likely benign	not specified	2016-03-28	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: Multiple conflicting assertions about splice impact; ExAC: 0.5%(36/6594) Finnish chromosomes
Fulgent Genetics, Fulgent Genetics	RCV000077384	SCV000575752	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-30	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000168529	SCV000586913	likely benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168529	SCV000593697	benign	not specified	2018-11-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579605	SCV000683813	benign	Hereditary cancer-predisposing syndrome	2014-12-05	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000045051	SCV000747802	likely benign	Hereditary breast ovarian cancer syndrome	2018-01-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000077384	SCV001138938	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656581	SCV001148967	benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656581	SCV001156934	benign	not provided	2023-08-21	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000074550	SCV001440715	likely benign	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000045051	SCV002026092	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798237	SCV002043389	benign	Breast and/or ovarian cancer	2021-04-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000579605	SCV002536278	benign	Hereditary cancer-predisposing syndrome	2020-05-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168529	SCV002550237	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000579605	SCV002662909	benign	Hereditary cancer-predisposing syndrome	2014-11-28	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000077384	SCV004016898	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003974931	SCV004797508	benign	BRCA2-related condition	2019-09-26	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Sharing Clinical Reports Project (SCRP)	RCV000077384	SCV000109181	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-04-05	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077384	SCV000146100	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-12-17	no assertion criteria provided	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000045051	SCV000257614	uncertain significance	Hereditary breast ovarian cancer syndrome	2015-07-21	flagged submission	clinical testing
Department of Medical Genetics, University Hospital of North Norway	RCV000077384	SCV000301443	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-05-01	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000168529	SCV000587534	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353785	SCV000591659	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The c.68-7T>A variant has been identified in ~20 families (and 14 affected probands) from our laboratory with breast cancer and 82 times in the UMD-BRCA2 database. In the literature, the variant was identified in 12 of 5594 proband chromosomes from individuals with breast and ovarian cancer, although an inadequate number of control chromosomes were tested to establish the variants' frequency in the general population such that the full spectrum of benign variation may not yet been defined for this gene, and increasing the possibility that this may be a benign variant (Hilton 2002, Muller 2011, Santarosa 1999, Thirthagiri 2008). The variant was identified by the ESP project (0.0015 in EU; 0.0002 in AA), and was identified in the Exome Aggregation Consortium (ExAC) database in all populations listed (European (Non-Finnish), East Asian, African, Latino, South Asian, European (Finnish)) with an overall frequency of 0.002, suggesting this may be a low frequency variant. In addition, this variant was identified by our laboratory in one individual who was homozygous for this variant who developed bilateral breast cancer late in life and the variant was suspected to segregate (in heterozygous form) with breast cancer in two other individuals in the family. However, homozygous deleterious variants of the BRCA2 gene have been demonstrated to cause Fanconi-Anemia, which was not reported in this individual, and increasing the likelihood that this variant is benign, but this information does not rule out the possibility that this variant could have contributed to the cancer in this family. The variant is listed in dbSNP database as coming from a "clinical source" (ID#: rs81002830) and had a frequency of 0.002 in the 1000 Genomes project. This variant was identified in ClinVar (by Invitae as Likely Benign, GeneDx as Benign, Sharing clinical reports project derived from Myriad reports as Uncertain significance (as of 2012 - more recently, in a personal communication Myriad has re-classified this variant as a polymorphism), by the BIC database as Uncertain significance. The c.68-7T>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 2 of 4 different programs. However, this information is not predictive enough to rule in or out pathogenicity. Studies have shown the increased rate of exon 3 skipping for this variant (20-30%), but this has also been observed in controls (Muller 2011, Thery 2011, Sanz 2010, Vreeswijk 2009, Houdayer 2012, Santorosa 1999). The c.68-7T>A variant and two other variants located at the same nucleotide position (c.68-7delT, and one c.68-78delAA) were all found to sometimes co-occur with a pathogenic BRCA2 mutation (Muller 2011), increasing the likelihood that this variant does not have clinical significance. In the UMD database, the variant was identified as co-occurring with another pathogenic variant 9x (4x in BRCA2 with: c.1796_1800delCTTAT (p.Ser599X) or c.5130_5133delTGTA (p.Tyr1710X)). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656581	SCV000778631	likely benign	not provided	2016-12-06	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000579605	SCV000787944	likely benign	Hereditary cancer-predisposing syndrome	2017-06-27	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077384	SCV004244239	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing