Submissions for variant NM_000059.4(BRCA2):c.5897A>G (p.His1966Arg)

gnomAD frequency: 0.00002  dbSNP: rs80358823

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001083441	SCV000072801	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130475	SCV000185342	likely benign	Hereditary cancer-predisposing syndrome	2019-01-21	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	RCV000586187	SCV000210623	likely benign	not provided	2020-08-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18284688, 17972171)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586187	SCV000600667	uncertain significance	not provided	2021-08-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509172	SCV000694913	uncertain significance	not specified	2022-12-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5897A>G (p.His1966Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250962 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5897A>G has been reported in the literature in individuals affected with breast and ovarian cancers (e.g. Lee_2008, Hondow_2011, Gorringe_2008, Santonocito_2020, Fanale_2021, Abdel-Razeq_2021, Patruno_2021, Abdel-Razeq_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and reported the variant with conflicting assessments, classifying the variant as unknown significance (n=2), likely benign (n=3), or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000130475	SCV000910850	benign	Hereditary cancer-predisposing syndrome	2017-02-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130475	SCV002536185	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-16	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130475	SCV003850761	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).
Sharing Clinical Reports Project (SCRP)	RCV000031587	SCV000054193	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-01-14	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031587	SCV000146727	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing