ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.985A>T (p.Asn329Tyr) (rs786203732)

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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 RCV000167164 SCV000217997 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000196902 SCV000254999 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces asparagine with tyrosine at codon 329 of the BRCA1 protein (p.Asn329Tyr). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 187436). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000759566 SCV000293976 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.985A>T at the cDNA level, p.Asn329Tyr (N329Y) at the protein level, and results in the change of an Asparagine to a Tyrosine (AAT>TAT). Using alternate nomenclature, this variant would be defined as BRCA1 1104A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Asn329Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Tyrosine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Asn329Tyr occurs at a position that is not conserved 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 Asn329Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000236714 SCV000591312 uncertain significance not specified 2012-11-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759566 SCV000888960 uncertain significance not provided 2018-01-04 criteria provided, single submitter clinical testing
Color RCV000167164 SCV000909393 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-17 criteria provided, single submitter clinical testing

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