Submissions for variant NM_007294.4(BRCA1):c.5513T>A (p.Val1838Glu)

dbSNP: rs80357107

Total submissions: 9

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, susceptibility to, 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, susceptibility to, 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.
Color Diagnostics, LLC DBA Color Health	RCV001181282	SCV001346392	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glutamic acid at codon 1838 in the BRCT2 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be defective in protein stability, phosphopeptide binding and transcriptional activation (PMID: 20516115), and in a cell proliferation assay (PMID: 30209399). This variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 18375895, 32322110, 33302456; Color internal data; kConFab, https://databases.lovd.nl/shared/individuals/00045959). Multifactorial analyses based on clinical and functional data have determined this variant to be disease-causing (PMID: 18375895, 21990134). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853026	SCV002115224	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-03-27	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 18375895, 21990134). Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 27272900, 30209399). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 55611). This missense change has been observed in individual(s) with clinical features of breast and ovarian hereditary cancer (PMID: 18497862, 26976419). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1838 of the BRCA1 protein (p.Val1838Glu).
Ambry Genetics	RCV001181282	SCV003875287	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-12-12	criteria provided, single submitter	clinical testing	The p.V1838E variant (also known as c.5513T>A), located in coding exon 22 of the BRCA1 gene, results from a T to A substitution at nucleotide position 5513. The valine at codon 1838 is replaced by glutamic acid, an amino acid with dissimilar properties. This nucleotide substitution is non-functional across multiple functional assays (Lee MS et al. Cancer Res, 2010 Jun;70:4880-90; Findlay GM et al. Nature, 2018 Oct;562:217-222). This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J Clin Oncol, 2016 May;34:1460-8). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 May;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077628	SCV000109431	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-02-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077628	SCV000145563	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000077628	SCV001237605	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro