Submissions for variant NM_007294.4(BRCA1):c.5044G>A (p.Glu1682Lys)

dbSNP: rs80356958

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112471	SCV000244378	benign	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 1 based on posterior probability = 0.0000976
GeneDx	RCV000616478	SCV000713911	likely benign	not specified	2017-03-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV001023465	SCV001185347	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-15	criteria provided, single submitter	clinical testing	The p.E1682K variant (also known as c.5044G>A), located in coding exon 15 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5044. The glutamic acid at codon 1682 is replaced by lysine, an amino acid with similar properties. This alteration has been reported to be found in trans with another BRCA1 pathogenic mutation (Judkins T et al. Cancer Res, 2005 Nov;65:10096-103). Multifactorial analyses determined that this alteration to be benign (Easton DF et al. Am J Hum Genet, 2007 Nov;81:873-83; Lindor NM et al. Hum Mutat, 2012 Jan;33:8-21). One protein functional study determined that this alteration was functional in protease sensitivity, peptide binding, peptide binding specificity, and transcriptional activity assays (Lee MS et al. Cancer Res, 2010 Jun;70:4880-90). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay and was measured to have a decrease in mRNA expression (Findlay GM et al. Nature, 2018 10;562:217-222). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001410968	SCV001613024	likely benign	Hereditary breast ovarian cancer syndrome	2019-03-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000616478	SCV004223272	uncertain significance	not specified	2023-11-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5044G>A (p.Glu1682Lys) results in a conservative amino acid change in BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251368 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5044G>A has been reported in the literature in unspecified individual(s) who underwent clinical BRCA1 screening, without strong evidence for causality (example, Judkins_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with at-least one pathogenic variant, at a homozygous state has been reported (BRCA1 c.3048_3052dup, p.Asn1018fs), providing supporting evidence for a benign role (described as c.3171ins5 by Judkins_2005). At least one publication reports experimental evidence evaluating an impact on protein function. Two of which showed no damaging effect of this variant on protein levels, colony formation, protease sensitivity, binding activity, transcription activity and structural stability in yeast or mammalian cells (Lee_2010, Thouvenot_2016). Meanwhile, a functional study via a high-throughput, genome editing, haploid cell survival assay evaluated this variant loss-of-function based on a decrease in mRNA expression (Findlay_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30209399, 16267036, 20516115, 27272900). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Benign, n=1, Likely benign, n=2, VUS, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112471	SCV000145272	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-06-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112471	SCV001237488	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro