Submissions for variant NM_000059.4(BRCA2):c.4585G>A (p.Gly1529Arg) (rs28897728)

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113324	SCV000244450	benign	Breast-ovarian cancer, familial 2	2015-08-10	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 = 0.000000000166
Invitae	RCV000044446	SCV000072459	benign	Hereditary breast and ovarian cancer syndrome	2020-12-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000113324	SCV000154094	benign	Breast-ovarian cancer, familial 2	2014-04-02	criteria provided, single submitter	literature only
GeneDx	RCV000656605	SCV000210607	likely benign	not provided	2020-10-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19471317, 11447276, 11873550, 26332594, 28651617, 28324225, 24323938, 25896959, 20694749, 22811390, 24055113, 21520273, 25637381, 25782689, 23231788, 20104584, 23034506, 15983021, 10551859, 19747923, 12442171, 21990134, 27741520, 27153395, 27376475, 28283652, 17924331, 29356034, 32426482, 32846166)
Ambry Genetics	RCV000162670	SCV000213117	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Pathway Genomics	RCV000113324	SCV000223766	likely benign	Breast-ovarian cancer, familial 2	2014-10-30	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories,University of Michigan	RCV000113324	SCV000267766	likely benign	Breast-ovarian cancer, familial 2	2016-04-21	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000353459	SCV000383702	likely benign	Fanconi anemia, complementation group D1	2019-09-23	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.
Illumina Clinical Services Laboratory,Illumina	RCV000113324	SCV000383703	likely benign	Breast-ovarian cancer, familial 2	2019-09-23	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044446	SCV000494387	benign	Hereditary breast and ovarian cancer syndrome	2015-04-06	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest causes a missense change in a conserved position with 4/4 in silico programs predicting a "deleterious" outcome (SNPs&Go not captured here due to low reliability index). The variant of interest has an observed allele frequency of 57/121370 (1/2127) in controls, which does not significantly exceed the maximum expect allele frequency for a pathogenic BRCA2 variant, 1/1333. However, the variant of interest has been found in cases to co-occur with multiple potential pathogenic BRCA2 (1 - c.5350_5351delAA (p.Asn1784HisfsX2) and 1 - c.8755_10257del (p.Gly2919fsX15)) and BRCA1 (1 - c.3226A>T (p.Arg1076X)) variants including internal LCA sample that co-occurred with a BRCA1 variant, c.3358_3359delGT (p.Val1120X scored DV). Although, functional studies show no impairment on exon splicing but conflicting evidence for a role in homologous recombination via recruitment of RAD51, however, this functional analysis has not been indepdently reproduced by other laboratories and their relevance to in-vivo mechanisms of pathogenicity have not been unequivocally established. Furthermore, multiple reputable databases (ARUP, UMD, BIC, SCRP, GeneDx and Ambry Genetics) and publications (Easton_2007 and Lindor_2012) classify the variant as likely benign/benign/neutral. . Therefore, taken together, the variant of interest is classified as benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000160225	SCV000538486	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.1%(42/66226) European; ClinVar: 8 B/LB
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001282554	SCV000602833	likely benign	none provided	2020-02-03	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000162670	SCV000683634	likely benign	Hereditary cancer-predisposing syndrome	2015-04-02	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113324	SCV000743301	likely benign	Breast-ovarian cancer, familial 2	2015-06-15	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113324	SCV000744459	benign	Breast-ovarian cancer, familial 2	2015-09-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000113324	SCV001139093	likely benign	Breast-ovarian cancer, familial 2	2019-05-28	criteria provided, single submitter	clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital	RCV000044446	SCV001775532	benign	Hereditary breast and ovarian cancer syndrome	2021-08-04	criteria provided, single submitter	clinical testing
Research and Development, ARUP Laboratories	RCV001642341	SCV001854804	benign	Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome	2020-01-20	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000113324	SCV000054096	benign	Breast-ovarian cancer, familial 2	2011-03-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113324	SCV000146453	benign	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148413	SCV000190112	likely benign	Breast and/or ovarian cancer	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000656605	SCV000591912	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Gly1529Arg variant was identified in 4 of 6448 proband chromosomes (frequency: 0.001) from individuals with breast or ovarian cancer (Borg 2010, Kauff 2008, Sinclair 2002). Two functional studies suggest that the variant affects binding with Rad51 (Chen 1999, Tal 2009), and one in silico study predicts that this variant may be deleterious using hierarchal modeling (Capanu 2011). However, there is conflicting evidence, two additional in silico studies using multifactorial-likelihood ratio models predict the variant to be neutral (Easton 2007, Lindor 2012). The variant was identified in dbSNP (ID: rs28897728) as “With Likely benign allele”, in Clinvitae database (classifications; benign and likely benign), Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database (classified as not pathogenic, of no clinical importance), COSMIC (in a medulloblastoma and endometrioid carcinoma), the ClinVar database (classification benign, reviewed by an expert panel, multiple submitters), GeneInsight COGR database (classifications of likely benign, benign, and uncertain significance by 4 clinical laboratories), the BIC database (75x with no clinical importance), and UMD (62x with a “neutral” classification, co-occurring with deleterious BRCA1, c.3226A>T, p.Arg1076X, BRCA2, c.5350_5351delAA, p.Asn1784HisfsX2, and BRCA2, c.8755_10257del, p.Gly2919fsx15 variants, increasing the likelihood that the p.Gly1529Arg variant does not have clinical significance. The variant was also identified in the 1000 Genomes Project in 3 of 5000 chromosomes (frequency: 0.0006), HAPMAP populations -EUR in 2 of 1006 chromosomes (frequency: 0.002) and AMR in 1 of 694 chromosomes (frequency: 0.0014), NHLBI GO Exome Sequencing Project in 6 of 8600 European American alleles (frequency: 0.0007), and the Exome Aggregation Consortium (March 14, 2016) in 51 of 120448 chromosomes (freq. 0.00042) in the following populations: European (Non-Finnish) in 42 of 66226 chromosomes (freq. 0.00063), South Asian in 6 of 16482 chromosomes (freq. 0.00036), Latino in 2 of 11536 chromosomes (freq. 0.00017), and other in 1 of 898 chromosomes (freq. 0.00011) but was not seen in African, East Asian, and Finnish populations. The p.Gly1529 residue is conserved across mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, Mutation Taster) suggest that the p.Gly1529Arg variant may impact the protein however this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656605	SCV000778676	likely benign	not provided	2015-10-07	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162670	SCV000787932	likely benign	Hereditary cancer-predisposing syndrome	2017-09-11	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000160225	SCV001799991	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute	RCV000160225	SCV001905956	benign	not specified		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000160225	SCV001958662	benign	not specified		no assertion criteria provided	clinical testing