Submissions for variant NM_000059.4(BRCA2):c.8359C>T (p.Arg2787Cys)

gnomAD frequency: 0.00001  dbSNP: rs41293517

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001088658	SCV000073504	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130122	SCV000184954	benign	Hereditary cancer-predisposing syndrome	2020-03-17	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	RCV000656804	SCV000329142	likely benign	not provided	2019-04-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19043619, 29394989, 25348012, 29884841)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656804	SCV000600798	uncertain significance	not provided	2023-06-19	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). Experimental studies report the variant does not affect BRCA2 homology-directed repair activity (PMIDs: 29394989 (2018), 29884841 (2019), 31131967 (2019)), however further studies are needed to understand the overall impact this variant has on BRCA2 function. The frequency of this variant in the general population, 0.000004 (1/251422 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Counsyl	RCV000113912	SCV000785084	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130122	SCV000903960	likely benign	Hereditary cancer-predisposing syndrome	2017-09-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000305632	SCV001363149	likely benign	not specified	2022-10-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8359C>T (p.Arg2787Cys) results in a non-conservative amino acid change located in the OB1 fold (IPR015187) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251422 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8359C>T has been reported in the literature in at least one individual affected with breast cancer, suspected of Hereditary Breast And Ovarian Cancer Syndrome (e.g. Moradian_2021, Bisgin_2022). However, in this individual and at least one other, co-occurrences with other pathogenic variants have been reported (BRCA2 c.1414C>T, p.Gln472X reported in Moradian_2021, Bisgin_2022 and BIC database; BRCA1 c.4612C>T, p.Gln1538X in BIC database; BRCA1 c.1407_1408delAA, p.Ser470ProfsX9 via internal testing), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Guidugli_2018). The results of this HDR assay showed no damaging effect for this variant. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Multiple laboratories reported the variant with conflicting assessments. The majority classified the variant as either benign (n=2) or likely benign (n=3), and the remaining classified it as VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Genetics and Molecular Pathology, SA Pathology	RCV000113912	SCV002761542	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-11-25	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113912	SCV000147333	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
King Laboratory, University of Washington	RCV000305632	SCV001251303	benign	not specified	2019-09-01	no assertion criteria provided	research
Center of Medical Genetics and Primary Health Care	RCV001269500	SCV001449142	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing