Submissions for variant NM_000059.4(BRCA2):c.5882G>A (p.Ser1961Asn)

gnomAD frequency: 0.00001  dbSNP: rs80358820

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044784	SCV000072797	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000128953	SCV000172831	likely benign	Hereditary cancer-predisposing syndrome	2018-11-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV001703439	SCV000512372	likely benign	not provided	2019-05-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23683081, 16758124, 15937982)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000439783	SCV000694914	uncertain significance	not specified	2023-10-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5882G>A (p.Ser1961Asn) results in a conservative amino acid change located in the BRCA2 repeat region, between the repeats BRC6 and BRC7 (IPR002093) of 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 8e-06 in 250986 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5882G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Blay_2013, Infante_2006, Velasco_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.3331_3334delCAAG, p.Gln1111fsX5 in the BIC database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=6) and VUS (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl	RCV000031585	SCV000784831	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128953	SCV000903520	benign	Hereditary cancer-predisposing syndrome	2016-12-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000031585	SCV001139129	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001703439	SCV002010348	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128953	SCV002536184	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-19	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000128953	SCV003850748	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001703439	SCV004220479	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 23683081 (2013), 16758124 (2006), 15937982 (2005)). Additionally, the variant has been characterized as being a variant of uncertain significance in a multifactorial likelihood study (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.000046 (1/21644 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.
Sharing Clinical Reports Project (SCRP)	RCV000031585	SCV000054191	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031585	SCV000146722	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-06-20	no assertion criteria provided	clinical testing