ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5513T>A (p.Val1838Glu) (rs80357107)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077628 SCV000244404 pathogenic Breast-ovarian cancer, familial 1 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077628 SCV000326350 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000480633 SCV000567434 pathogenic not provided 2016-05-26 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5513T>A at the cDNA level, p.Val1838Glu (V1838E) at the protein level, and results in the change of a Valine to a Glutamic Acid (GTG>GAG). This variant, also published as BRCA1 5632T>A using alternate numbering, has been observed in at least three individuals with a history of breast cancer (Spurdle 2008, Waddell 2008, Tung 2016). BRCA1 Val1838Glu has been reported to have a functional impact in several in vitro functional assays looking at protease sensitivity, phosphopeptide binding activity/specificity, and transcription (Lee 2010). Additionally, this variant was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants. BRCA1 Val1838Glu 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 Valine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Val1838Glu occurs at a position that is conserved across species and is located in the BRCT2 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 the currently available evidence, we consider BRCA1 Val1838Glu to be pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077628 SCV000109431 uncertain significance Breast-ovarian cancer, familial 1 2012-02-29 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077628 SCV000145563 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing

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