Submissions for variant NM_000059.4(BRCA2):c.8573A>G (p.Gln2858Arg)

gnomAD frequency: 0.00002  dbSNP: rs80359114

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045562	SCV000073575	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131683	SCV000186719	likely benign	Hereditary cancer-predisposing syndrome	2019-03-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000656806	SCV000210478	likely benign	not provided	2021-05-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19043619, 21990134, 18375895, 21702907, 21990165, 16905680, 28678401, 28283652, 25348012, 10923033, 29641532, 29884841, 31131967)
Eurofins Ntd Llc (ga)	RCV000656806	SCV000227605	uncertain significance	not provided	2015-01-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656806	SCV000296596	uncertain significance	not provided	2023-06-21	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2), 28283652 (2017), 16905680 (2007)), head and neck cancer (PMID: 28678401 (2017)), and healthy individuals (PMID: 28283652 (2017)). Additionally, the variant is reported to have no impact on BRCA2 function (PMID: 29884841 (2019)), however additional studies are needed to determine the global effect of this variant. The frequency of this variant in the general population, 0.000031 (4/128990 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	RCV000113963	SCV000785686	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131683	SCV000902975	likely benign	Hereditary cancer-predisposing syndrome	2015-12-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192535	SCV001360746	benign	not specified	2020-11-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8573A>G (p.Gln2858Arg) results in a conservative amino acid change located in the Tower domain (IPR015205) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251234 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8573A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example, Simard_2007, Spurdle_2008, Shimelis_2017). These data do not allow any conclusion about variant significance. Co-occurrences with pathogenic variants have been reported in the BIC database (BRCA1 c.1054G>T, p.Glu352X; BRCA1 c.2035A>T, p.Lys679X), providing supporting evidence for a benign role. In addition, a multifactorial probability based model utilized for performing systematic assessment of variants of unknown significance in the BRCA genes, which includes analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicts this variant to be likely not pathogenic or of little clinical significance (Lindor_2012). One publication, Hart_2018, reports the HDR activity of this variant to be similar to that of wild-type and classifies the variant as neutral. Seven ClinVar submitters (evaluation after 2014) cite this variant as likely benign (n=4) and as uncertain significance (n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the lack of evidence supporting an actionable outcome as outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798241	SCV002043588	uncertain significance	Breast and/or ovarian cancer	2022-04-14	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113963	SCV000147404	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing