Submissions for variant NM_000059.4(BRCA2):c.2817C>T (p.Thr939=)

gnomAD frequency: 0.00001  dbSNP: rs367921107

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000494816	SCV000578881	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	RCV000165865	SCV000216614	likely benign	Hereditary cancer-predisposing syndrome	2014-09-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Invitae	RCV001081793	SCV000253006	benign	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000430864	SCV000512351	benign	not specified	2015-07-06	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.
Color Diagnostics, LLC DBA Color Health	RCV000165865	SCV000683503	benign	Hereditary cancer-predisposing syndrome	2016-07-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759593	SCV000889012	likely benign	not provided	2022-01-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000430864	SCV000918834	likely benign	not specified	2021-07-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759593	SCV001160453	benign	not provided	2023-02-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000759593	SCV001501464	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BP7
Sema4, Sema4	RCV000165865	SCV002535531	likely benign	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003917571	SCV004728142	likely benign	BRCA2-related condition	2020-12-28	criteria provided, single submitter	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353444	SCV000591827	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Thr939= variant was identified in 1 of 3050 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer (Caux-Moncoutier 2011). The variant was also identified in dbSNP (ID: rs367921107) as With Likely benign allele, ClinVar (classified as benign by GeneDx; classified as likely benign by ENIGMA, Ambry Genetics, Invitae), Clinvitae, LOVD 3.0 (2X), UMD-LSDB (13X as unclassified variant), databases. The variant was not identified in BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 13 of 245704 chromosomes at a frequency of 0.000053 (Genome Aggregation Consortium Feb 27, 2017). The p.Thr939= 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, the variant was identified with a co-occurring pathogenic BRCA2 variant (c.8488-1G>A), increasing the likelihood that the c.2817C>T variant does not have clinical significance (Santos 2014). 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.