Submissions for variant NM_000059.4(BRCA2):c.7504C>T (p.Arg2502Cys)

gnomAD frequency: 0.00100  dbSNP: rs55716624

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045233	SCV000073246	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000168602	SCV000108638	likely benign	not specified	2018-01-30	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	RCV000131136	SCV000186071	benign	Hereditary cancer-predisposing syndrome	2020-01-22	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.
CSER _CC_NCGL, University of Washington	RCV000148436	SCV000190135	uncertain significance	Breast and/or ovarian cancer	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Eurofins Ntd Llc (ga)	RCV000034459	SCV000226200	uncertain significance	not provided	2014-11-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034459	SCV000296686	benign	not provided	2022-09-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000077403	SCV000488326	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-12	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168602	SCV000538498	uncertain significance	not specified	2016-06-23	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: Frequency; ClinVar: 2 LB, 7 VUS
Genetic Services Laboratory, University of Chicago	RCV000168602	SCV000593754	likely benign	not specified	2017-07-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034459	SCV000695071	benign	not provided	2016-02-11	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Cysteine (C). 4/5 in silico tools predict the variant to be benign. It was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.029%. It is most prevalent in the African subpopulation with an observed allele frequency of 0.29% which exceeds the maximal expected allele frequency of a disease causing BRCA2 allele (0.075%) indicating the variant to be benign. The variant was also observed in HBOC spectrum patients, however without strong evidence for pathogenicity. A functional study reported the variant not to have an effect on normal splicing. Moreover, BIC reports co-occurrence with multiple pathogenic BRCA1 variants c.3764_3765insA (p.Asn1255fsX12), and c.5324T>G (p.Met1775Arg) and c. 5074G>A (p.Asp1692Asn) further supporting a benign impact. Clinical diagnostic centers classify variant as Uncertain/Likely Benign/Benign via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as Benign.
Mendelics	RCV000045233	SCV000838854	benign	Hereditary breast ovarian cancer syndrome	2023-08-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000168602	SCV000883514	likely benign	not specified	2019-05-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131136	SCV000902720	benign	Hereditary cancer-predisposing syndrome	2016-05-24	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000045233	SCV001450728	likely benign	Hereditary breast ovarian cancer syndrome	2020-12-03	criteria provided, single submitter	clinical testing	The BRCA2 c.7504C>T (p.Arg2502Cys) missense change has a maximum subpopulation frequency of 0.32% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/13-32930633-C-T). This frequency is higher than would be expected for a pathogenic variant in BRCA2 (BS1; PMID: 28166811). This variant affects a nucleotide that is not highly conserved and is predicted to be benign by multiple in silico algorithms (BP4). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP4.
Sema4, Sema4	RCV000131136	SCV002531861	likely benign	Hereditary cancer-predisposing syndrome	2021-05-17	criteria provided, single submitter	curation
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000045233	SCV004167628	benign	Hereditary breast ovarian cancer syndrome	2023-10-19	criteria provided, single submitter	curation	(BA1, BS3, BP4_strong). According to the ACMG standard criteria we chose these criteria: BP4 (strong benign): Bayes Del noAF (-0.0527), BS3 (strong benign): Richardson et al., 2021: neutral / final classification: benign (BA1, BS3, BP4_strong), BA1 (stand-alone benign): gnomAD: AF AFR: 0.003065
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000148436	SCV004240352	likely benign	Breast and/or ovarian cancer	2022-12-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003924893	SCV004743322	likely benign	BRCA2-related condition	2022-02-01	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).
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034459	SCV000043226	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000077403	SCV000109200	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2007-02-09	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077403	SCV000147108	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000034459	SCV000592116	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Arg2502Cys variant was identified in 1 of 1144 proband chromosomes (frequency: 0.0.001) from individuals or families with cancer syndromes (Johnston 2012). The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in dbSNP (ID: rs55716624 “With Uncertain significance allele”, with a minor allele frequency of 0.0004 (2/5000 chromosomes tested in 1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server) in 15 of 4406 African Americans (frequency: 0.0034) and not found in European Americans, Exome Aggregation Consortium database (March 14, 2016) in 36 of 121024 chromosomes (frequency:0.003) from a population of African (30/10322), European (Non-Finnish-4/66524), Latino (1/11538) individuals and not in East Asian , South Asian and European (Finnish) or Other individuals. The p.Arg2502Cys variant was also identified in HGMD, LOVD (2x as unknown), classified as an Uncertain significance variant by 6 separate submitters to the ClinVar database (the Sharing Clinical Reports Project derived from Myriad reports, GeneDX, BIC, Ambry Genetics, CSER_CC_NCGL, Biesecker Laboratory – ClinSeq Project_NHGRI), GeneInsight COGR 1x (classified as uncertain by a clinical laboratory), the BIC database (17x with unknown clinical importance), and UMD (6x as an uncertain variant). Note the variant co-occurred 2x with 2 other variants of unknown significance i.e. c.1798T>C, p.Tyr600His VUS and c.IVS10+9delGT VUS. The p.Arg2502 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The p.Arg2502Cys variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, an assessment of 1,433 missense variants of unknown clinical significance, a likelihood ratio was computed based on a hypothesis that the variants were equivalent to an average deleterious mutation compared with neutral with respect to odds risk to other factors such as family history and co-occurrence. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS. The combined odds ratio for the variant was 21:1 and predicted causal, an odds ratio of 100:1 being neutral (Easton 2007). In another study (Karchin 2008), the authors are in disagreement with the conclusion of the Easton study. They have presented a new computational approach for analyzing the impact of missense changes in the DNA-binding domains of the cancer susceptibility protein BRCA2 that uses information from protein sequence, structure, and sequence conservation. They concluded the 2502Cys variant as neutral. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
True Health Diagnostics	RCV000131136	SCV000787950	likely benign	Hereditary cancer-predisposing syndrome	2018-01-05	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077403	SCV004243767	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-02	no assertion criteria provided	clinical testing