Submissions for variant NM_000059.4(BRCA2):c.1786G>C (p.Asp596His)

gnomAD frequency: 0.00025  dbSNP: rs56328701

Total submissions: 39

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083088	SCV001161606	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000066
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043882	SCV000071895	benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000083088	SCV000154038	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only
Ambry Genetics	RCV000131138	SCV000186074	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: 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000083088	SCV000195962	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000514736	SCV000210568	likely benign	not provided	2021-03-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17997147, 24728327, 32426482, 21952622, 21520273, 25637381, 23231788, 17513806, 27153395, 26306726, 28678401, 26517685, 28439188, 20104584, 18284688, 16284991, 31131967)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768622	SCV000219305	benign	Breast and/or ovarian cancer	2016-03-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120309	SCV000224768	likely benign	not specified	2015-04-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000292009	SCV000383635	likely benign	Fanconi anemia complementation group D1	2018-08-30	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000083088	SCV000383636	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-08-30	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120309	SCV000538484	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.1% (45/65250) European; ClinVar: 5 LB, 3 B
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000120309	SCV000586930	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514736	SCV000610856	likely benign	not provided	2017-02-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131138	SCV000683446	likely benign	Hereditary cancer-predisposing syndrome	2015-02-06	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000083088	SCV000743263	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000083088	SCV000744414	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120309	SCV000805655	benign	not specified	2017-07-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000514736	SCV000885088	benign	not provided	2023-09-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514736	SCV000892063	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP4, BS2
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000514736	SCV001133693	likely benign	not provided	2019-01-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000083088	SCV001139009	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000043882	SCV002012451	likely benign	Hereditary breast ovarian cancer syndrome	2021-08-26	criteria provided, single submitter	clinical testing	The BRCA2 c.1786G>C (p.Asp596His) missense change has a maximum subpopulation frequency of 0.064% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/13-32907401-G-C). In silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in seven women older than 70 years of age who have never had cancer (BS2_supporting; https://whi.color.com/variant/13-32907401-G-C). It has also been reported in individuals with a personal or family history of breast cancer (PMID: 17513806, 28439188, 20104584), ovarian cancer (PMID: 17997147, 18559594, 16284991), and head neck squamous cell carcinoma (PMID: 28678401). This variant has been reported to co-occur with pathogenic variants in BRCA1 and BRCA2 (BP2; UMD database). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS2_supporting, BP2, BP4.
Genetic Services Laboratory, University of Chicago	RCV000120309	SCV002071326	likely benign	not specified	2019-10-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131138	SCV002533261	likely benign	Hereditary cancer-predisposing syndrome	2020-11-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120309	SCV002550285	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490600	SCV002795896	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-03-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000083088	SCV004846969	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
ITMI	RCV000120309	SCV000084461	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000083088	SCV000115162	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083088	SCV000145933	not provided	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148417	SCV000190116	likely benign	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353780	SCV000591765	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asp596His variant was identified in 7 of 7970 proband chromosomes (frequency: 0.001) from individuals or families with ovarian and breast cancer (Borg 2010, Brozek 2007, Lee 2008, Machado 2007, Pal 2005); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also identified by our laboratory in 2 individuals with breast cancer. The variant was identified by the Exome Variant Server project in 5 of 12995 European American/African American alleles (frequency: 0.0004), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Asp596 residue is conserved across most mammals, but not across lower organisms. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. An in silico analysis study by Lee (2008) classified this variant as low-frequency unclassified variant with medium to high risk in selected computational predictive programs; however, a population study by Pal (2005) noted that a tumour with the variant had low malignant potential. This variant was identified in dbSNP (ID: rs56328701) “With untested allele”, HGMD, ClinVar database, the BIC database (50X with no clinical importance), and UMD (44X as a neutral variant). In UMD the c.1786G>C variant was identified with five different co-occurring pathogenic BRCA1 and BRCA2 variants, increasing the likelihood that the p.Asp596His variant does not have clinical significance. In addition, the variant was classified as a benign by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000083088	SCV000733233	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000514736	SCV000778646	benign	not provided	2017-04-20	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120309	SCV001800392	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120309	SCV001906061	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120309	SCV001957883	benign	not specified		no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000083088	SCV004228378	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Strong)+BP1(Strong)+BP5(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
BRCAlab, Lund University	RCV000083088	SCV004244229	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing