Submissions for variant NM_000059.4(BRCA2):c.865A>G (p.Asn289Asp)

dbSNP: rs766173

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045592	SCV000073605	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000164485	SCV000215132	likely benign	Hereditary cancer-predisposing syndrome	2018-05-10	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.
Counsyl	RCV000031759	SCV000488144	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000589996	SCV000512335	likely benign	not provided	2020-09-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24853695, 26483394, 25896959, 24504028, 29258903, 28814288, 27165220, 28324225)
Color Diagnostics, LLC DBA Color Health	RCV000164485	SCV000683990	likely benign	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488352	SCV000695170	likely benign	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.865A>G (p.Asn289Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 314878 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.865A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome or other types of cancer (Wappenschmidt_2006, Cunningham_2014, Yang _2015, DArgenio_2015, Hu_2015, Tung_2015, Meisel_2017, Santonocito_2020, de Oliveira_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with one specific pathogenic variant (BRCA2 c.5864C>A, p.Ser1955X) have been reported in patients, providing supporting evidence for a benign role (kConFab data, BIC data, Internal data, Tung_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24504028, 25896959, 26483394, 28324225, 36243179, 32438681, 25186627, 26535628, 35534704). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=5) and likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589996	SCV001470257	uncertain significance	not provided	2024-09-23	criteria provided, single submitter	clinical testing	The BRCA2 c.865A>G (p.Asn289Asp) variant has been reported in the published literature to co-occur with the BRCA2 c.5864C>A (p.Ser1955*) pathogenic variant in multiple individuals (PMID: 25186627 (2015), BIC database (https://research.nhgri.nih.gov/projects/bic)), suggesting the c.865A>G (p.Asn289Asp) variant is not the primary cause of disease. However, this variant by itself has also been reported in individuals with breast/ovarian cancer (PMIDs: 32438681 (2020), 32284662 (2019), 28324225 (2017), 27165220 (2016), 25896959 (2015), 24504028 (2014)), and pancreatic cancer (PMID: 26483394 (2015)). The frequency of this variant in the general population, 0.000027 (3/110406 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000589996	SCV002010303	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798054	SCV002043599	likely benign	Breast and/or ovarian cancer	2021-02-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164485	SCV002531966	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164485	SCV003848093	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000045592	SCV005374678	likely benign	Hereditary breast ovarian cancer syndrome	2024-08-13	criteria provided, single submitter	curation	According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose this criterion: BP1 (strong benign): (SpliceAI <=0.1)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589996	SCV005875917	likely benign	not provided	2024-09-18	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031759	SCV000054367	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-07-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031759	SCV000145782	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000589996	SCV000778638	uncertain significance	not provided	2017-12-20	no assertion criteria provided	clinical testing