ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.429A>C (p.Glu143Asp) (rs397507228)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229242 SCV000289799 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-11-13 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 143 of the BRCA1 protein (p.Glu143Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs397507228, ExAC <0.01%). This variant has been observed in an individual with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333). However, in that individual pathogenic allele was also identified in a different gene (BRCA2), which suggests that this c.429A>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 37582). 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. 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 RCV000481623 SCV000566796 uncertain significance not provided 2015-06-01 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.429A>C at the cDNA level, p.Glu143Asp (E143D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAC). Using alternate nomenclature, this variant would be defined as BRCA1 548A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu143Asp 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 Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. BRCA1 Glu143Asp occurs at a position that is not conserved and is not located in a known functional domain (Narod 2004, Borg 2010, Roy 2012, UniProt). 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 Glu143Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000571835 SCV000660960 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Sharing Clinical Reports Project (SCRP) RCV000031163 SCV000053763 uncertain significance Breast-ovarian cancer, familial 1 2008-07-31 no assertion criteria provided clinical testing

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