Submissions for variant NM_000059.4(BRCA2):c.8360G>A (p.Arg2787His)

gnomAD frequency: 0.00002  dbSNP: rs80359078

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212273	SCV000210470	likely benign	not provided	2018-09-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19043619, 25980754, 25348012, 21990134, 11929857, 24323938, 24372583, 26158448, 26659599, 27211102, 23108138, 29020732, 29394989, 29310832, 28814288, 29988080, 29884841)
Ambry Genetics	RCV000214554	SCV000274666	likely benign	Hereditary cancer-predisposing syndrome	2019-10-29	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	RCV000031739	SCV000488563	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214554	SCV000689119	likely benign	Hereditary cancer-predisposing syndrome	2021-11-02	criteria provided, single submitter	clinical testing
Mendelics	RCV005234817	SCV001139214	likely benign	Hereditary cancer	2025-02-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174961	SCV001338441	likely benign	not specified	2025-01-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8360G>A (p.Arg2787His) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 282802 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (3.5e-05 vs 0.00075), allowing no conclusion about variant significance. Multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Lindor_2012, Guidugli_2013). c.8360G>A has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer as well as in one individual with a history of LS-associated cancer and/or colorectal polyps (Riahi_2015, Yurgelun_2015, Eoh_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In addition, at least one co-occurrence with another pathogenic variant has been reported (BRCA1 c.928C>T, p.Gln310Ter), providing supporting evidence for a benign role (Eoh_2017). Functional studies report this variant has no impact on protein function based on HDR assay results (Guidugli_2012, Hart_2018, Mesman_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29310832, 28814288, 29020732, 29580235, 29394989, 23108138, 24323938, 29884841, 19043619, 21990134, 29988080, 24372583, 27211102, 11929857, 25980754). ClinVar contains an entry for this variant (Variation ID: 38156). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212273	SCV001469718	uncertain significance	not provided	2019-09-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001442600	SCV001645551	likely benign	Hereditary breast ovarian cancer syndrome	2024-09-12	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001174961	SCV002551816	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803079	SCV004845642	likely benign	BRCA2-related cancer predisposition	2024-07-29	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031739	SCV000054346	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-02-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031739	SCV000147334	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212273	SCV001743468	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212273	SCV001955849	uncertain significance	not provided		no assertion criteria provided	clinical testing