Submissions for variant NM_000059.4(BRCA2):c.2538A>C (p.Ser846=)

gnomAD frequency: 0.00009  dbSNP: rs11571654

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113057	SCV000578016	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0049 (South Asian), derived from ExAC (2014-12-17).
Invitae	RCV000167797	SCV000072024	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000044011	SCV000167345	benign	not specified	2014-02-12	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.
Ambry Genetics	RCV000162905	SCV000213392	likely benign	Hereditary cancer-predisposing syndrome	2014-08-11	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.
Counsyl	RCV000113057	SCV000220710	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-09-19	criteria provided, single submitter	literature only
Illumina Laboratory Services, Illumina	RCV000113057	SCV000383653	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000378892	SCV000383654	likely benign	Fanconi anemia complementation group D1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167797	SCV000494432	benign	Hereditary breast ovarian cancer syndrome	2015-08-24	criteria provided, single submitter	clinical testing	Variant Summary: The variant of interest causes a synonymous change involving a non-conserved nucleotide with Mutation Taster predicting the variant to be a "polymorphism." 3/5 in silico programs via Alamut predict no significant effect on splicing and the removal of an ESE binding site, SRp40, although these predictions have yet to be functionally assessed. The variant of interest was observed in a large, broad control population, ExAC with an allele frequency of 98/120626 (1/1231, including 2 homozygotes), which exceeds the maximum expected allele frequency for a BRCA2 variant of 1/1333. The variant of interest has been reported in affected individuals via publications, including a reported co-occurrence with another pathogenic BRCA1 variant (5404delG; De Silva et al 2001). In addition, multiple reputable databases/clinical laboratories (BIC, GeneDx, Ambry Genetics, and Invitae) cite the variant with a classification of "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as benign.
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000044011	SCV000586935	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162905	SCV000683490	benign	Hereditary cancer-predisposing syndrome	2015-12-28	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113057	SCV000743274	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-10	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113057	SCV000744427	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000044011	SCV000805674	benign	not specified	2017-05-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656592	SCV001159041	benign	not provided	2021-01-14	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000167797	SCV002026078	benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798228	SCV002042517	likely benign	Breast and/or ovarian cancer	2023-05-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162905	SCV002535504	benign	Hereditary cancer-predisposing syndrome	2020-10-06	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000656592	SCV002545109	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BP7, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000044011	SCV002550306	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000113057	SCV004016830	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113057	SCV000146064	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-10-28	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353445	SCV000591809	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ser846Ser 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. Two of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this is not very predictive of pathogenicity. The variant was identified in 5 of 5234 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Alsop 2012, Caux-Moncoutier 2011, Soumittra 2009); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs11571654) “With Benign, untested allele”, BIC (1X with no clinical importance), the ClinVar database (classified as benign by BIC and GeneDx; classification not provided by Invitae), and UMD (11X as an unclassified variant). The variant was identified in the 1000 Genomes Project in 5 chromosomes (frequency: 0.001), HAPMAP-GIH in 2 of 176 chromosomes (frequency: 0.011), Exome Variant Server ESP project in 2 of 8598 European American alleles. The variant was identified in several populations in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014), with the following allele counts and frequencies: South Asian (82/16468 alleles, frequency: 0.005), Latino (7/11470 alleles, frequency: 0.0006), European (Non-Finnish) (8/66348 alleles, frequency; 0.0001, and “Other” (1/904 alleles, frequency: 0.001). Notably two of the individuals tested in the ExAC database were homozygous for the variant (one South Asian and one Latino), increasing the likelihood that this variant may not have clinical significance. In addition, Myriad classifies this as a polymorphism (personal communication). In summary, based on the above information, this variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656592	SCV000778653	likely benign	not provided	2017-04-07	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162905	SCV000805239	likely benign	Hereditary cancer-predisposing syndrome	2018-05-09	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000656592	SCV001905727	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656592	SCV001952208	likely benign	not provided		no assertion criteria provided	clinical testing