Submissions for variant NM_000059.4(BRCA2):c.5839C>T (p.Pro1947Ser)

gnomAD frequency: 0.00002  dbSNP: rs80358812

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044772	SCV000072785	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132548	SCV000187646	likely benign	Hereditary cancer-predisposing syndrome	2019-01-14	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768631	SCV000324875	uncertain significance	Breast and/or ovarian cancer	2015-08-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000113492	SCV000487847	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781083	SCV000918894	uncertain significance	not specified	2019-12-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5839C>T (p.Pro1947Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250962 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5839C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Li_2017, Li_2018, Bhaskaran_2019). 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. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and cited the variant as uncertain significance (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985552	SCV001133842	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00022 (4/18390 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast, ovarian, adrenal cancer (PMIDs: 28664449 (2017), 30078507 (2018), 30093976 (2018)), and in healthy controls (PMIDs: 30078507 (2018), 33471991 (2021; see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2). This variant also co-occurred with a pathogenic variant in the BRCA2 gene in an individual in our internal patient population, suggesting it may not be the primary cause of disease. 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.
Color Diagnostics, LLC DBA Color Health	RCV000132548	SCV001359118	likely benign	Hereditary cancer-predisposing syndrome	2021-09-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000985552	SCV001805645	uncertain significance	not provided	2023-04-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 6067C>T; This variant is associated with the following publications: (PMID: 28664449, 30078507, 30093976, 30212499, 30702160, 31825140, 32467295)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132548	SCV003850717	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).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113492	SCV000146710	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250517	SCV002520812	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only