Submissions for variant NM_000059.4(BRCA2):c.2589T>A (p.Asn863Lys)

gnomAD frequency: 0.00020  dbSNP: rs80358521

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044020	SCV000072033	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130583	SCV000185455	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	RCV001284078	SCV000512348	likely benign	not provided	2020-09-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25348012, 27656653)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000427575	SCV000694613	likely benign	not specified	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2589T>A (p.Asn863Lys) results in a non-conservative amino acid change in 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 4.8e-05 in 227084 control chromosomes, exclusively observed within the African subpopulation at a frequency of 0.0007 in the gnomAD database. This frequency is slightly lower than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.00075). In addition, the variant was reported in 3 / 2559 women of African ancestry who were older than 70 years of age and never had cancer (FLOSSIES database). c.2589T>A has been also reported in the literature in an African American woman affected with breast cancer (Pal 2015) and a patient with an unspecified personal and/or family history of breast cancer (Pereira_2022). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as benign (n=1), likely benign (n=4), or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000044020	SCV000838776	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130583	SCV000903075	benign	Hereditary cancer-predisposing syndrome	2016-04-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284078	SCV001469666	likely benign	not provided	2023-01-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000427575	SCV002069516	likely benign	not specified	2021-06-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130583	SCV002535508	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-01	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130583	SCV003848427	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).
PreventionGenetics, part of Exact Sciences	RCV003952377	SCV004774550	likely benign	BRCA2-related condition	2023-11-21	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).
Sharing Clinical Reports Project (SCRP)	RCV000031375	SCV000053980	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031375	SCV000146076	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing