ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5327C>T (p.Pro1776Leu) (rs398122695)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160003 SCV000210214 uncertain significance not provided 2016-08-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5327C>T at the cDNA level, p.Pro1776Leu (P1776L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). Using alternate nomenclature this variant would be defined as BRCA1 5446C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Pro1776Leu 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 Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Pro1776Leu occurs at a position that is not conserved and is located in the second BRCT domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Pro1776Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000217660 SCV000273041 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-03 criteria provided, single submitter clinical testing
Counsyl RCV000077164 SCV000488264 uncertain significance Breast-ovarian cancer, familial 1 2016-02-09 criteria provided, single submitter clinical testing
Invitae RCV000558496 SCV000636027 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-06-30 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1776 of the BRCA1 protein (p.Pro1776Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs398122695, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 91647). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Color RCV000217660 SCV000683287 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077164 SCV000108961 uncertain significance Breast-ovarian cancer, familial 1 2007-11-14 no assertion criteria provided clinical testing

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