Submissions for variant NM_000059.4(BRCA2):c.4258G>T (p.Asp1420Tyr)

gnomAD frequency: 0.00609  dbSNP: rs28897727

Total submissions: 42

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083103	SCV000244448	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	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 = 0.000102
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044377	SCV000072390	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000083103	SCV000154044	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only
GeneDx	RCV000120339	SCV000167364	benign	not specified	2013-10-09	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000083103	SCV000195982	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162541	SCV000212944	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735549	SCV000219337	benign	Breast and/or ovarian cancer	2016-01-06	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120339	SCV000225172	benign	not specified	2014-11-12	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000162541	SCV000267017	likely benign	Hereditary cancer-predisposing syndrome	2016-02-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162541	SCV000292117	benign	Hereditary cancer-predisposing syndrome	2015-03-05	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000044377	SCV000296855	benign	Hereditary breast ovarian cancer syndrome	2015-08-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000083103	SCV000383697	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-02-12	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044377	SCV000494324	benign	Hereditary breast ovarian cancer syndrome	2014-04-07	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034440	SCV000510802	likely benign	not provided	2017-01-24	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Fulgent Genetics, Fulgent Genetics	RCV000083103	SCV000575731	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-26	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000120339	SCV000586948	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034440	SCV000602780	benign	not provided	2023-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034440	SCV000692771	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS2
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000083103	SCV000743297	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	RCV000083103	SCV000744454	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120339	SCV000805705	benign	not specified	2017-06-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000083103	SCV001139086	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000044377	SCV002026101	benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120339	SCV002069010	benign	not specified	2017-12-04	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000044377	SCV002515273	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162541	SCV002533860	benign	Hereditary cancer-predisposing syndrome	2020-03-26	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120339	SCV002550334	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000083103	SCV004016851	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000034440	SCV005236053	benign	not provided		criteria provided, single submitter	not provided
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034440	SCV000043208	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000120339	SCV000084491	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000083103	SCV000115177	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083103	SCV000146395	not provided	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion provided	clinical testing
Pathway Genomics	RCV000083103	SCV000187734	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-24	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353826	SCV000591897	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Asp1420Tyr variant has been previously reported in the literature in 203 of 18968 proband chromosomes (frequency of 0.011) with breast and ovarian cancer, and was also identified in 109 of 8530 (frequency of 0.013) control chromosomes increasing the likelihood that this is a low frequency benign variant It is listed in dbSNP database as coming from a "clinical source" (ID#: rs28897727) with a global minor allele frequency (MAF) of 0.001/2, and has an average heterozygosity of 0.008+/-0.062, increasing the likelihood that it is a benign variant. The Asp1420 residue is not highly conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. However, this information is not predictive enough to rule out pathogenicity. Functional studies have shown that compared to the wild-type protein, the p.Asp1420Tyr variant showed similar repair capacity and protein interactions, particularly with RAD51 (Davies_2001_11239456, Galkin_2005_15937124, Kuznetsov_2008_18607349). In addition, in two studies, one of which was a case control study, the allele frequency was higher in controls compared to the proband (Dombernowsky_2009_19661094, Stuppia_2003_12872265), thereby increasing the likelihood that this variant does not have clinical significance. Myriad genetics classifies this variant as a polymorphism, increasing the likelihood this variant is benign. In summary, we cannot rule out the possibility that this variant may contribute to the phenotype in these individuals, but based on the above information this variant is classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000083103	SCV000733255	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000034440	SCV000778674	benign	not provided	2016-12-12	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162541	SCV000787930	benign	Hereditary cancer-predisposing syndrome	2018-01-05	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000083103	SCV000863687	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120339	SCV001797615	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120339	SCV001906316	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120339	SCV001958459	benign	not specified		no assertion criteria provided	clinical testing