Submissions for variant NM_000059.4(BRCA2):c.3055C>G (p.Leu1019Val)

gnomAD frequency: 0.00012  dbSNP: rs55638633

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031398	SCV000244434	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	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 = 0.00000000714
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079288	SCV000072121	benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000755878	SCV000210585	likely benign	not provided	2021-02-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20104584, 12474142, 25637381, 21990134, 12845657, 21671020, 24323938, 23231788, 27376475, 21520273, 26332594, 17924331, 28283652, 30995915, 32444794, 32426482, 31851867, 31131967)
Ambry Genetics	RCV000162553	SCV000212963	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: 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044108	SCV000538473	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: All publications in HGMD list as non-pathogenic; ExAC: 16/66172 European chromosomes
Color Diagnostics, LLC DBA Color Health	RCV000162553	SCV000683523	likely benign	Hereditary cancer-predisposing syndrome	2015-03-12	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031398	SCV000743281	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-05-26	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031398	SCV000744435	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162553	SCV000747809	likely benign	Hereditary cancer-predisposing syndrome	2018-01-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755878	SCV000883521	benign	not provided	2019-10-30	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769690	SCV000901104	likely benign	Breast and/or ovarian cancer	2016-12-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000031398	SCV001139055	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000755878	SCV001148979	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP4, BS3:Moderate
Sema4, Sema4	RCV000162553	SCV002533759	likely benign	Hereditary cancer-predisposing syndrome	2021-03-16	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000044108	SCV002550318	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031398	SCV004016853	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031398	SCV000054003	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-06-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031398	SCV000146160	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148419	SCV000190118	likely benign	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353411	SCV000591845	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Leu1019Val variant was identified in 4 of 5690 proband chromosomes (frequency: 0.001) from individuals with breast or prostate cancer (Balia 2011 21671020, Capanu 2011, DeSanjose 2003, Edwards 2003). The variant was listed in dbSNP (ID: rs55638633) “With untested allele”, with one variant allele identified in the 1000 Genomes Project (frequency: 0.0005), and was identified in of 8590 European American alleles in the NHLBI Exome Sequencing Project (Exome Variant Server). However, this low number of observations and frequency is not substantive enough to determine the prevalence of this variant in the general population. The variant was also identified in HGMD, LOVD, the BIC database (22X with unknown clinical importance), and UMD (11X as a neutral variant). In UMD, the variant was identified in co-occurrence with two different pathogenic BRCA2 mutations and two different pathogenic BRCA1 mutations, increasing the likelihood that the p.Leu1019Val variant does not have clinical significance. The p.Leu1019 residue is conserved in mammals but not in lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. This information is not very predictive of pathogenicity. One functional assay found that expression of the variant did not increase spontaneous recombination in human cells, in a manner similar to expression of wild-type BRCA2 (Balia 2011). A yeast-based assay found that the variant demonstrated similar to wild-type homologous recombination (Spugnesi 2013). Three in silico models predicted the variant to be non-pathogenic or of no clinical significance (Capanu 2011, Easton 2007, Lindor 2012 21990134). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000044108	SCV001905814	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000044108	SCV001957586	benign	not specified		no assertion criteria provided	clinical testing