Submissions for variant NM_000059.4(BRCA2):c.517-4C>G

gnomAD frequency: 0.00008  dbSNP: rs81002804

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001083460	SCV000072603	benign	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000212206	SCV000167325	benign	not specified	2014-04-07	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	RCV000131488	SCV000186476	likely benign	Hereditary cancer-predisposing syndrome	2018-06-27	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000044590	SCV000296597	benign	not provided	2023-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212206	SCV000694837	likely benign	not specified	2024-05-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.517-4C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.1e-05 in 1590354 control chromosomes, predominantly at a frequency of 0.00063 within the African or African-American subpopulation in the gnomAD database (v4.1 dataset). This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00075), allowing no clear conclusions about variant significance. However, the variant was also reported from the southern part of Africa with even higher allele frequencies, e.g. 0.014 (3/208 alleles; in the GenomeAsia 100K database) and 0.028 (Oosthuizen_2021), supporting a benign role for the variant. c.517-4C>G has been reported in the literature in individuals affected with breast- and/or ovarian cancer (Pal_2015, Abulkhair_2018, Santonocito_2020), but was also found in controls (Wagner_1999). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 51802). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000113731	SCV000785180	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131488	SCV000903207	likely benign	Hereditary cancer-predisposing syndrome	2015-08-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000113731	SCV001138969	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113731	SCV001269105	uncertain significance	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001111541	SCV001269106	uncertain significance	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001083460	SCV002025959	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000113731	SCV002030109	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2021-06-04	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000131488	SCV002533927	likely benign	Hereditary cancer-predisposing syndrome	2022-03-16	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001083460	SCV005045406	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-14	criteria provided, single submitter	clinical testing
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004584182	SCV005068375	likely benign	Inherited breast cancer and ovarian cancer	2024-05-02	criteria provided, single submitter	clinical testing	BS1_Strong,BP4
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113731	SCV000147051	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113731	SCV000297535	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-09-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355912	SCV001550933	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 c.517-4C>G variant was identified in 2 of 1554 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer and was present in 1 of 190 control chromosomes (frequency: 0.005) from healthy individuals (Abulkhair 2018, Pal 2015, Wagner 1999). The variant was also identified in dbSNP (ID: rs81002804) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx and Sharing Clinical Reports Project (SCRP); as likely benign by Ambry Genetics and two other submitters; and as uncertain significance by three submitters), LOVD 3.0 and the BIC Database (2x with unknown clinical importance). The variant was not identified in UMD-LSDB database. It was identified in control databases in 10 of 277034 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 9 of 24024 chromosomes (freq: 0.0004) and Other in 1 of 6460 chromosomes (freq: 0.0002), while the variant was not observed in the Latino, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.517-4C>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions or position -3 and -5 to -12, which are part of the splicing consensus sequence and sometimes affect splicing. 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.
BRCAlab, Lund University	RCV000113731	SCV004243859	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing