Submissions for variant NM_000059.4(BRCA2):c.7413A>G (p.Thr2471=)

gnomAD frequency: 0.00002  dbSNP: rs138067005

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495312	SCV000579060	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Ambry Genetics	RCV000213502	SCV000273910	likely benign	Hereditary cancer-predisposing syndrome	2015-02-16	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.
GeneDx	RCV000417816	SCV000515759	benign	not specified	2015-06-23	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.
Baylor Genetics	RCV000457254	SCV000541057	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083358	SCV000560482	likely benign	Hereditary breast ovarian cancer syndrome	2024-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000417816	SCV000695059	likely benign	not specified	2019-08-21	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000495312	SCV000744516	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586071	SCV000887914	likely benign	not provided	2022-12-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586071	SCV000892067	likely benign	not provided	2022-03-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BP7
Color Diagnostics, LLC DBA Color Health	RCV000213502	SCV000903484	likely benign	Hereditary cancer-predisposing syndrome	2016-06-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000213502	SCV002531854	likely benign	Hereditary cancer-predisposing syndrome	2021-10-31	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000417816	SCV002551479	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357473	SCV001552955	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Thr2471= variant was identified in 3 of 3698 proband chromosomes (frequency: 0.001) from individuals or families with unilateral breast cancer or hereditary breast cancer (Borg 2010, Claes 2004). The variant was also identified in dbSNP (ID: rs138067005) as "With Likely benign allele" , ClinVar (classified as benign by GeneDx and Baylor Miraca Genetics Laboratories Study description; as likely benign by Invitae, Ambry Genetics, Enigma and DNA and Cytogenetics Diagnostics Unit, Erasmus Medical Center; as uncertain significance by Integrated Genetics/Laboratory Corporation of America), Clinvitae, LOVD 3.0 (4x conflicting interpretation of pathogenicity), and in UMD-LSDB (1x as unclassified variant) databases. The variant was not identified in GeneInsight-COGR, Cosmic, BIC Database, ARUP Laboratories, or Zhejiang University Database databases. The variant was identified in control databases in 8 of 245878 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant observed in European population in 8 of 111442 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Thr2471= 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000417816	SCV001906455	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000417816	SCV001957731	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532780	SCV004713190	likely benign	BRCA2-related disorder	2022-02-17	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).