ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2662C>T (p.His888Tyr) (rs80357480)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081135 SCV000075927 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129905 SCV000184723 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-05 criteria provided, single submitter clinical testing The p.H888Y variant (also known as c.2662C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2662. The histidine at codon 888 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in families with suspected hereditary breast cancer (Meyer P et al. Hum. Mutat. 2003 Sep; 22(3):259; Miramar MD et al. Breast Cancer Res. Treat. 2008 Nov; 112(2):353-8). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. However, other in silico prediction models have predicted conflicting results for the pathogenicity of this variant (Martelotto LG et al. Genome Biol. 2014; 15(10):484). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047914 SCV000698971 uncertain significance not specified 2020-07-16 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2662C>T (p.His888Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251050 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance c.2662C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins 2005, Meyer 2003, Miramar 2008, Kraus 2016, Alvarez 2017, Gabaldo 2017, Tsaousis_2019). These reports however do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant has been reported (in the UMD database: BRCA2 c.5073dupA (p.Trp1692fsX3)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (i.e. 8 calling it as a VUS, 1 as likely benign, and 1 as benign). Based on the evidence outlined above, 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 Health, Inc 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 2020-03-19 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
Mayo Clinic Laboratories, Mayo Clinic RCV000589310 SCV001716307 uncertain significance not provided 2020-11-30 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000589310 SCV000591401 uncertain significance not provided no assertion criteria provided clinical testing

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