Submissions for variant NM_000059.4(BRCA2):c.1011C>T (p.Asn337=)

gnomAD frequency: 0.00006  dbSNP: rs41293473

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)	RCV000112874	SCV000578713	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/).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080288	SCV000071729	benign	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163333	SCV000213867	likely benign	Hereditary cancer-predisposing syndrome	2014-09-22	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.
Eurofins Ntd Llc (ga)	RCV000724514	SCV000224770	uncertain significance	not provided	2015-01-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000112874	SCV000489615	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000173639	SCV000512336	benign	not specified	2015-04-15	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	RCV000467442	SCV000541067	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163333	SCV000683394	likely benign	Hereditary cancer-predisposing syndrome	2016-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000724514	SCV000888971	likely benign	not provided	2023-05-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173639	SCV000918934	likely benign	not specified	2020-07-09	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001080288	SCV002026061	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163333	SCV002533190	likely benign	Hereditary cancer-predisposing syndrome	2022-01-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000173639	SCV002761140	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149669	SCV003838144	likely benign	Breast and/or ovarian cancer	2022-04-14	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000112874	SCV004016850	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537184	SCV004756176	likely benign	BRCA2-related disorder	2019-06-12	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).
CeGaT Center for Human Genetics Tuebingen	RCV000724514	SCV005093556	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BP7
Breakthrough Genomics, Breakthrough Genomics	RCV000724514	SCV005215516	likely benign	not provided		criteria provided, single submitter	not provided
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112874	SCV000145804	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-06-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353646	SCV000591725	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Asn372Asn variant was identified in 1 of 762 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer (Fackenthal 2012). The variant was also identified in dbSNP (ID: rs41293473) “With uncertain significance allele”, with a minor allele frequency of 0.0002 (1000 Genomes Project), Clinvitae database, COSMIC 1X, the ClinVar database 5X with conflicting interpretations (2X as likely benign and 3X with uncertain significance), the BIC database (1X with unknown clinical importance), and the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 2 of 10050 chromosomes (frequency: 0.0002) from a population of African individuals and in 2 of 66314 chromosomes (frequency: 3.02x10-3) from a population of European (Non-Finnish) individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified in our laboratory with a co-occurring pathogenic BRCA2 variant (p.Phe1559LeufsX9), increasing the likelihood that the p.Asn337Asn variant does not have clinical significance. The p.Asn337Asn 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 summary, based on the above information, we lean towards a more benign role for this variant. This variant is classified as benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000724514	SCV001906289	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724514	SCV001972638	likely benign	not provided		no assertion criteria provided	clinical testing