Submissions for variant NM_000059.4(BRCA2):c.7505G>A (p.Arg2502His)

gnomAD frequency: 0.00004  dbSNP: rs56070345

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083136	SCV001161616	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00054
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081947	SCV000073247	benign	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131692	SCV000186728	benign	Hereditary cancer-predisposing syndrome	2017-12-22	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000588836	SCV000210652	likely benign	not provided	2021-03-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10486320, 24504028, 19043619, 24772314, 21702907, 25583476, 18824701, 10882858, 25415331, 22505045, 28222693, 27616075, 28263838, 30696104)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588836	SCV000602788	likely benign	not provided	2018-04-16	criteria provided, single submitter	clinical testing	The BRCA2 c.7505G>A; p.Arg2502His variant (rs56070345) is reported in patients with breast and ovarian cancer (Akbari 2011, Gayther 1999, Spearman 2008), but also in an unaffected individual (Balabanski 2014). This variant is reported in ClinVar (Variation ID: 52345) and found in the general population with an overall allele frequency of 0.007% (17/246182 alleles) in the Genome Aggregation Database. The arginine at codon 2502 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Additionally, this variant has been previously identified by our laboratory in a patient who also carries a pathogenic truncating BRCA1 variant. Based on available information, this variant is considered to be likely benign. REFERENCES Akbari MR et al. Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes. J Med Genet. 2011 Nov;48(11):783-6. Balabanski L et al. Next-generation sequencing of BRCA1 and BRCA2 in breast cancer patients and control subjects. Mol Clin Oncol. 2014 May;2(3):435-439. Gayther SA et al. The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes. Am J Hum Genet. 1999 Oct;65(4):1021-9. Spearman AD et al. Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol. 2008 Nov 20;26(33):5393-400.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045234	SCV000695072	benign	not specified	2022-10-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7505G>A (p.Arg2502His) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.1e-05 in 252472 control chromosomes, predominantly at a frequency of 0.00029 within the South Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7505G>A has been reported in the literature in individuals affected with breast- or ovarian cancer (e.g. Akbari_2011, Gayther_1999, Spearman_2008, Bolognesi_2014, Cunningham_2014, Davies_2018, Kraus_2016, Momozawa_2018), but also in controls (Bolognesi_2014, Balabanski_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variant(s) have been observed at our laboratory and in prominent databases (UMD-BRCA1 c.5096G>A, p.Arg1699Gln; Our laboratory-BRCA1 c.68_69delAG; ARUP laboratories-BRCA1, pathogenic variant is not specified), providing supporting evidence for a benign role. Two publications reported experimental evidence evaluating an impact on protein function, and demonstrated no damaging effect on splicing (Houdayer_2012), and no effect on the BRCA2/DSS1 interaction (Caleca_2019). Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with a predominant consensus as benign/likely benign (n=11) (VUS, n=2). Based on the evidence outlined above, the variant was classified as benign.
Counsyl	RCV000083136	SCV000784917	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-02-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000588836	SCV000805764	likely benign	not provided	2017-10-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131692	SCV000902828	benign	Hereditary cancer-predisposing syndrome	2015-12-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588836	SCV001133901	likely benign	not provided	2018-08-09	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000588836	SCV002010330	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001081947	SCV002025820	benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000045234	SCV002064780	likely benign	not specified	2021-12-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131692	SCV002531862	likely benign	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000588836	SCV005050910	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS3:Supporting, BS1
Sharing Clinical Reports Project (SCRP)	RCV000083136	SCV000115210	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083136	SCV000147109	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing