ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5896C>T (p.His1966Tyr) (rs80358822)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000225745 SCV000072800 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131689 SCV000186725 likely benign Hereditary cancer-predisposing syndrome 2020-10-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000044787 SCV000210622 likely benign not specified 2017-11-02 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.
Vantari Genetics RCV000131689 SCV000267020 likely benign Hereditary cancer-predisposing syndrome 2015-11-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044787 SCV000694915 uncertain significance not specified 2019-06-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5896C>T (p.His1966Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250972 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5896C>T has been reported in the literature in affected individuals (Caux-Moncoutier_2011, Spearman_2008, Lu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.213-11T>G and BRIP1 c.2392C>T (p.Arg798X) in two internal samples), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as VUS (2x) or likely benign (4x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl RCV000031586 SCV000785127 uncertain significance Breast-ovarian cancer, familial 2 2017-05-01 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761156 SCV000891072 uncertain significance B lymphoblastic leukemia lymphoma with hyperdiploidy 2016-12-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131689 SCV000910982 likely benign Hereditary cancer-predisposing syndrome 2017-04-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000044787 SCV001160596 uncertain significance not specified 2019-05-21 criteria provided, single submitter clinical testing The BRCA2 c.5896C>T; p.His1966Tyr variant (rs80358822) is reported in the literature in a large cohort of individuals with a personal or family history of breast or ovarian cancer, but no specific phenotype data is available (Caux-Moncoutier 2011). This variant is reported as uncertain or likely benign by multiple laboratories in ClinVar (Variation ID: 38005), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The histidine at codon 1966 is weakly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.His1966Tyr variant is uncertain at this time. References: Caux-Moncoutier V et al. EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. Hum Mutat. 2011 Mar;32(3):325-34.
Sharing Clinical Reports Project (SCRP) RCV000031586 SCV000054192 likely benign Breast-ovarian cancer, familial 2 2010-02-11 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031586 SCV000146726 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356911 SCV001552198 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.His1966Tyr variant was not identified in the literature nor was it identified in the Cosmic, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs80358822) as With other allele, ClinVar (classified as likely benign by Invitae, GeneDx, Vantari Genetics, SCRP; classified as uncertain significance by Ambry Genetics, BIC), Clinvitae (conflicting interpretations of pathogenicity), MutDB, LOVD 3.0 (3X predicted neutral), UMD-LSDB (4X unclassified variant), BIC Database (5X with unknown clinical significance), ARUP Laboratories (uncertain significance), databases. The variant was identified in control databases in 3 of 277056 chromosomes at a frequency of 0.000011 (Genome Aggregation Consortium Feb 27, 2017). The p.His1966 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Breast cancer type 2 susceptibility protein functional domain increasing the likelihood that it may have clinical significance. 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.

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