ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1798T>C (p.Tyr600His) (rs75419644)

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Total submissions: 19
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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 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).
Invitae RCV000043889 SCV000071902 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 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: 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120310 SCV000224761 benign not specified 2014-11-04 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000043889 SCV000383640 likely benign Hereditary breast and ovarian cancer syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Health, Inc 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 2 2015-09-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282163 SCV000883513 likely benign none provided 2020-01-31 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642661 SCV001854695 likely benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
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 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
Human Genetics - Radboudumc,Radboudumc RCV000588236 SCV001952519 likely benign not provided no assertion criteria provided clinical testing

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