Submissions for variant NM_000059.4(BRCA2):c.2803G>A (p.Asp935Asn)

gnomAD frequency: 0.00054  dbSNP: rs28897716

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044061	SCV000072074	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000083092	SCV000154040	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only
GeneDx	RCV000120336	SCV000167347	benign	not specified	2013-11-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000129118	SCV000183834	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: 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	RCV000768590	SCV000219318	likely benign	Breast and/or ovarian cancer	2023-02-07	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120336	SCV000225169	likely benign	not specified	2014-09-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000083092	SCV000383659	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-10-17	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.
Illumina Laboratory Services, Illumina	RCV000397028	SCV000383660	likely benign	Fanconi anemia complementation group D1	2018-10-17	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	RCV000120336	SCV000538472	likely benign	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: Multiple publications classify as VUS/not pathogenic; ExAC: 0.1% (57/66390) European chromosomes
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679163	SCV000602765	benign	not provided	2023-09-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129118	SCV000683501	likely benign	Hereditary cancer-predisposing syndrome	2015-04-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000083092	SCV000743276	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	RCV000083092	SCV000744429	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679163	SCV000805677	likely benign	not provided	2017-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679163	SCV000892065	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP4
Mendelics	RCV000083092	SCV001139042	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120336	SCV002068999	likely benign	not specified	2021-12-16	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000044061	SCV002515257	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000129118	SCV002535524	benign	Hereditary cancer-predisposing syndrome	2021-07-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120336	SCV002550310	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000083092	SCV002761667	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-02-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496688	SCV002797355	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	2022-03-04	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000044061	SCV004228031	benign	Hereditary breast ovarian cancer syndrome	2023-11-21	criteria provided, single submitter	clinical testing
ITMI	RCV000120336	SCV000084488	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000083092	SCV000115166	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083092	SCV000146113	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353683	SCV000591825	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2, EXON11, c.2803G>A, p.Asp935Asn variant was identified in 5 of 5884 chromosomes (frequency: 0.001) from individuals with breast, ovarian or prostate cancer and was absent in 208 control chromosomes (Beetstra 2006, Capanu 2011, Edwards 2003, Soegaard 2008, Wagner 1999); 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 in dbSNP (ID:rs28897716) “With non-pathogenic allele”, HGMD, LOVD, the BIC database (106X as a variant with no clinical importance), and UMD (53X as a neutral variant). In UMD, the variant was listed as co-occurring with four different pathogenic BRCA2 mutations and one pathogenic BRCA1 mutation, increasing the likelihood that this variant does not have clinical significance. In addition, Spurdle (2008) identified a homozygote with the variant who did not have clinical features of Fanconi anemia, further suggesting that this variant is neutral. In addition, the variant was listed in the 1000 Genomes Project with a frequency of 0.0005 and in the NHLBI Exome Sequencing Project with frequency of 0.0007, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Asp935 residue is not conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein. Furthermore, three in silico studies predicted the variant to have no clinical significance or effect on risk (Capanu 2011, Lindor 2012, Moghadasi 2013). 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	RCV000083092	SCV000733239	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120336	SCV001906046	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120336	SCV001956556	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000679163	SCV002035455	likely benign	not provided		no assertion criteria provided	clinical testing