Submissions for variant NM_000059.4(BRCA2):c.2138A>T (p.Gln713Leu)

gnomAD frequency: 0.00138  dbSNP: rs55816687

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083754	SCV000071963	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000679159	SCV000108605	likely benign	not provided	2021-05-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26332594, 24055113, 15744044, 12474142, 24728327, 19491284, 23231788, 12491487, 25556971, 22034289, 25637381, 28814288, 18284688)
Ambry Genetics	RCV000131496	SCV000186485	benign	Hereditary cancer-predisposing syndrome	2018-09-11	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077272	SCV000195967	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679159	SCV000805666	likely benign	not provided	2017-07-11	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120312	SCV000859227	likely benign	not specified	2018-01-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679159	SCV000885100	likely benign	not provided	2017-07-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679159	SCV000889004	benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131496	SCV000902740	benign	Hereditary cancer-predisposing syndrome	2016-05-24	criteria provided, single submitter	clinical testing
Mendelics	RCV000077272	SCV001139022	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001083754	SCV002026073	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120312	SCV002070369	benign	not specified	2021-05-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131496	SCV002533297	benign	Hereditary cancer-predisposing syndrome	2020-12-08	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001083754	SCV004014899	benign	Hereditary breast ovarian cancer syndrome	2023-02-14	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000679159	SCV005215519	likely benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000120312	SCV000084464	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000077272	SCV000109069	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-03-24	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077272	SCV000146011	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000077272	SCV000187737	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-12-11	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148430	SCV000190129	uncertain significance	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353536	SCV000591791	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Gln713Leu variant was identified in 51 of 1748 proband chromosomes (frequency: 0.03) from individuals or families with prostate, breast and ovarian cancer (Edwards 2003, Fackenthal 2012, Trujillano 2015). The variant was also identified in dbSNP (ID: rs55816687) as “With Uncertain significance, other allele”, Clinvitae database (conflicting interpretations of pathogenicity), the ClinVar database (classified as benign by Invitae; classified as likely benign by GeneDx, Ambry Genetics, MMGLUM, Pathway Genomics; classified as uncertain significance by CSER_CC_NCGL, SCRP, BIC), the BIC database (10x with unknown clinical importance), UMD (28x with a “unclassified variant” classification) and Fanconi Anemia Mutation Database (LOVD). This variant was identified in the 1000 Genomes Project in 12 of 5000 chromosomes (frequency: 0.002), NHLBI GO Exome Sequencing Project in 19 of 4406 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 61 of 120866 chromosomes (freq. 0.0005) in the following populations: African in 60 of 10122 chromosomes (freq. 0.006), Latino in 1 of 11476 chromosomes (freq. 0.0001), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Gln713 residue is not conserved in mammals and three out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; loss of splicing site at a non-splice site consensus sequence. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as likely benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000679159	SCV001905798	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000679159	SCV001930080	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120312	SCV001959046	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679159	SCV001972808	likely benign	not provided		no assertion criteria provided	clinical testing