Submissions for variant NM_000059.4(BRCA2):c.1798T>C (p.Tyr600His)

gnomAD frequency: 0.00170  dbSNP: rs75419644

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112974	SCV001161578	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00546 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043889	SCV000071902	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000588236	SCV000108602	likely benign	not provided	2021-05-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 27741520, 22874498, 22034289, 25801821, 27208206, 29668487)
Ambry Genetics	RCV000131135	SCV000186068	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.
Eurofins Ntd Llc (ga)	RCV000120310	SCV000224761	benign	not specified	2014-11-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000043889	SCV000383640	likely benign	Hereditary breast ovarian cancer syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000298855	SCV000383641	likely benign	Fanconi anemia	2016-06-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120310	SCV000593704	likely benign	not specified	2017-04-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131135	SCV000683450	likely benign	Hereditary cancer-predisposing syndrome	2014-12-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588236	SCV000694565	benign	not provided	2016-10-05	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.1798T>C (p.Tyr600His) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 58/118492 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0058115 (56/9636). This frequency is about 8 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), evidence that this is a benign polymorphism found primarily in the populations of African origin. The variant was reported to co-occur with a pathogenic BRCA2 variant (p.Lys944X, UMD), another evidence of the benign nature of this variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000112974	SCV000744417	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588236	SCV000883513	likely benign	not provided	2021-10-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131135	SCV002533264	likely benign	Hereditary cancer-predisposing syndrome	2021-06-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120310	SCV002550289	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112974	SCV004846971	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
ITMI	RCV000120310	SCV000084462	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112974	SCV000145941	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2001-10-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353993	SCV000591769	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Tyr600His variant was not identified in the literature. The variant was identified by our laboratory in 1 individual with breast cancer. This variant was identified in dbSNP (ID: rs75419644) “With other allele”, with a minor allele frequency of 0.001 (5 of 5000 chromosomes in1000 Genomes Project). In NHLBI Exome Sequencing Project (Exome Variant Server) the variant was identified in in 24 of 4400 African American alleles (frequency: 0.005) and not found in European American alleles. The variant was identified in Exome Aggregation Consortium database (March 14, 2016) in 58 of 118492 chromosomes (frequency: 0.0005) from a population of African (56/9636 alleles), Latino (2/11458 alleles) and not found in European (Non-Finnish), East Asian, South Asian, European (Finnish) and Other individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in ClinVar database with conflicting interpretations: as benign by Invitae, Emory Genetics Laboratory and Ambry Genetics; as likely benign by GeneDX; as uncertain significance by Molecular Genetics Diagnostic Laboratory, Children’s Hospital of Eastern Ontario and BIC. ITMI did not provide a classification. The variant was identified in the BIC database 1x with uncertain clinical importance and in UMD 10x as an unknown variant. In UMD the variant was identified with two co-occurring unknown significance BRCA2 variants (c.1909+9delGT and c.7504C>T, p.Arg2502Cys). The p.Tyr600 residue is not conserved in mammals and the variant amino acid Histidine is present in rats, increasing the likelihood that this variant does not have clinical significance. All five computational analyses (SIFT, AlignGVGD, BLOSUM, PolyPhen-2, MutationTaster) do not suggest a high likelihood of impact to the protein. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
True Health Diagnostics	RCV000131135	SCV000787919	likely benign	Hereditary cancer-predisposing syndrome	2018-01-05	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000588236	SCV001906264	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588236	SCV001952519	likely benign	not provided		no assertion criteria provided	clinical testing