ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2662C>T (p.His888Tyr) (rs80357480)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000589310 SCV000075927 likely benign not provided 2019-02-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129905 SCV000184723 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000589310 SCV000210134 uncertain significance not provided 2019-01-03 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2662C>T at the cDNA level, p.His888Tyr (H888Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). This variant, also published as BRCA1 2781C>T using alternate nomenclature, has been observed in at least four individuals with breast cancer (Meyer 2003, Judkins 2005, Miramar 2008). BRCA1 His888Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 His888Tyr occurs at a position that is not conserved and is located within the DNA binding domain and in a region reported to interact with BASC and RAD51 (Narod 2004, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 His888Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768614 SCV000324815 uncertain significance Breast and/or ovarian cancer 2016-02-29 criteria provided, single submitter clinical testing
Counsyl RCV000111910 SCV000488138 uncertain significance Breast-ovarian cancer, familial 1 2016-02-19 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000047914 SCV000591401 uncertain significance not specified 2016-03-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589310 SCV000698971 uncertain significance not provided 2017-03-07 criteria provided, single submitter clinical testing Variant summary: This c.2662C>T (p.His888Tyr) alters a non-conserved nucleotide and 4/4 in silico tools predict a benign outcome (SNP&GO not captured here due to low reliability index). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00004. This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.001). The variant was identified in several individuals from HBOC families without strong evidence for causality and was reported to co-occur with a deleterious BRCA2 variant c.5073dup (p.Trp1692MetfsX3). Multiple reputable databases/clinical laboratories cite the variant with classification of VUS. Taking together, the variant was classified as VUS-Possibly Benign.
GeneKor MSA RCV000129905 SCV000821918 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color RCV000129905 SCV000910804 benign Hereditary cancer-predisposing syndrome 2015-12-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589310 SCV001133532 uncertain significance not provided 2019-02-08 criteria provided, single submitter clinical testing
Mendelics RCV000111910 SCV001140571 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111910 SCV000144502 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing

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