Submissions for variant NM_000059.4(BRCA2):c.6322C>T (p.Arg2108Cys) (rs55794205)

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113572	SCV001161523	benign	Breast-ovarian cancer, familial 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 = 0.000248
Invitae	RCV000044911	SCV000072924	benign	Hereditary breast and ovarian cancer syndrome	2020-12-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129227	SCV000183981	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.
GeneDx	RCV000034453	SCV000210627	likely benign	not provided	2020-09-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21671020, 22713736, 24728327, 28477318, 28324225, 18284688, 30254663, 17972177, 25782689, 24323938, 24489791, 22703879, 21520273, 23469205, 23328489, 18627636, 20104584, 25777348, 26183948, 22874498, 15172753, 24504028, 28222693, 27376475, 29061375, 28664449, 28392550, 28651617, 29302806, 21218378, 27882536, 30093976, 32072338)
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000735585	SCV000219376	benign	Breast and/or ovarian cancer	2016-03-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000113572	SCV000220889	likely benign	Breast-ovarian cancer, familial 2	2014-11-16	criteria provided, single submitter	literature only
Michigan Medical Genetics Laboratories,University of Michigan	RCV000113572	SCV000267793	benign	Breast-ovarian cancer, familial 2	2016-04-21	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000113572	SCV000383736	likely benign	Breast-ovarian cancer, familial 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina	RCV000384925	SCV000383737	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	RCV000044911	SCV000494352	benign	Hereditary breast and ovarian cancer syndrome	2015-04-30	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000129227	SCV000683773	likely benign	Hereditary cancer-predisposing syndrome	2015-04-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113572	SCV000743318	likely benign	Breast-ovarian cancer, familial 2	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113572	SCV000744486	likely benign	Breast-ovarian cancer, familial 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000120335	SCV000805739	benign	not specified	2017-08-17	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000034453	SCV001248280	likely benign	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Research and Development, ARUP Laboratories	RCV001642546	SCV001854878	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
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034453	SCV000043220	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000120335	SCV000084487	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113572	SCV000146824	uncertain significance	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto	RCV000120335	SCV000587835	benign	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000120335	SCV000592042	benign	not specified		no assertion criteria provided	clinical testing	The p.Arg2108Cys variant has been reported in the literature in 13/16,018 proband chromosomes from individuals with hereditary breast and/or ovarian cancer, although no control chromosomes were tested to establish the variant's frequency in the general population (Balia 2011, Capanu 2011, Purnomosari 2007, Borg 2010, Thirthagiri 2008, Jalkh 2012). There is conflicting evidence in the literature regarding its pathogenicity. It has been identified in the BIC database (x22) with unknown clinical importance, and in the LOVD and UMD databases (x5). The variant was identified in an individual who also had a pathogenic BRCA2 mutation c.5835_5842dup (p.Cys1948TyrfsX18) (UMD), and this finding increases the likelihood that the p.Arg2108Cys variant does not have clinical significance (notably compound heterozygous variants in the BRCA2 gene are expected to cause fanconi anemia but the phenotype was not provided in this case). In a functional assay that evaluated the effect of the transient overexpression of the p.Arg2108Cys variant on spontaneous homologous recombination (HR) in a HeLa cell line, the variant increased HR as much as a pathogenic variant G2748D, which led the authors to classify it as possibly pathogenic (Balia 2011), but the relevance of these findings in a cell model to the in-vivo organism remains questionable. It is listed in dbSNP database (ID#:rs55794205) as coming from a "clinical source" with a global minor allele frequency (MAF) of 0.002/5. Another variant at this position (p.Arg2108His) has been observed 126 times in the BIC database with unknown clinical significance, but this relatively high frequency may suggest that the variant is a common benign variant. In addition, this p.Arg2108 residue is not conserved in mammals and the variant amino acid Cys (Cysteine) is present in monkey, mouse, rat, cat and dog, increasing the likelihood that a change to this amino acid does not have functional significance. Computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not very predictive of pathogenicity. Myriad genetics reports this variant as a polymorphism (personal communication). In summary, based on the above information. This variant meets our lab's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000034453	SCV000778696	likely benign	not provided	2017-04-21	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735585	SCV000863723	uncertain significance	Breast and/or ovarian cancer	2013-03-15	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute	RCV000034453	SCV001905985	likely benign	not provided		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000034453	SCV001956829	likely benign	not provided		no assertion criteria provided	clinical testing