ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.535T>C (p.Tyr179His) (rs587781761)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129980 SCV000184804 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000657128 SCV000294070 uncertain significance not provided 2017-07-27 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.535T>C at the cDNA level, p.Tyr179His (Y179H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAC>CAC). Using alternate nomenclature, this variant would be defined as BRCA1 654T>C. This variant was observed in at least one individual undergoing BRCA1 and BRCA2 testing at a commercial laboratory (Judkins 2005). BRCA1 Tyr179His was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Tyr179His occurs at a position that is conserved in mammals and is located in a region known to interact with multiple proteins (Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Tyr179His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000239018 SCV000296441 uncertain significance Breast-ovarian cancer, familial 1 2016-03-11 criteria provided, single submitter clinical testing
Invitae RCV000464515 SCV000549365 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-22 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 179 of the BRCA1 protein (p.Tyr179His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs587781761, ExAC 0.001%). This variant has been reported in a high risk individual for breast and ovarian cancer (PMID: 16267036). This variant has also been observed in an individual with breast cancer (Invitae). However, in that individual, a pathogenic allele was also identified in BRCA1, which suggests that this c.535T>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 141458). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000236482 SCV000591278 uncertain significance not specified 2013-11-15 criteria provided, single submitter clinical testing
Color RCV000129980 SCV000683304 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-01 criteria provided, single submitter clinical testing

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