Submissions for variant NM_007294.4(BRCA1):c.3868A>G (p.Lys1290Glu)

gnomAD frequency: 0.00001  dbSNP: rs80357254

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759529	SCV000210160	uncertain significance	not provided	2018-07-19	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.3868A>G at the cDNA level, p.Lys1290Glu (K1290E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). Using alternate nomenclature, this variant would be defined as BRCA1 3987A>G. This variant was observed in several individuals with a personal and/or family history of breast and/or ovarian cancer (Minucci 2015, Azzollini 2016, Alemar 2017). BRCA1 Lys1290Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the SCD domain and a region known to interact with multiple other proteins (Narod 2004, Clark 2012, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Lys1290Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000218431	SCV000274418	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-03	criteria provided, single submitter	clinical testing	The p.K1290E variant (also known as c.3868A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3868. The lysine at codon 1290 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in Italian breast and/or ovarian cancer patients (Minucci A et al. Expert Rev. Mol. Diagn., 2015 Aug;15:1383-403; Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71), as well as in a cohort of 418 Brazilian individuals who met testing criteria for Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Alemar B et al. PLoS ONE, 2017 Nov;12:e0187630). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000234532	SCV000289789	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1290 of the BRCA1 protein (p.Lys1290Glu). This variant is present in population databases (rs80357254, gnomAD 0.002%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 26306726, 27062684, 29161300, 32438681). ClinVar contains an entry for this variant (Variation ID: 91617). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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.
Counsyl	RCV000077134	SCV000785413	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-25	criteria provided, single submitter	clinical testing
Mendelics	RCV000234532	SCV000839245	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759529	SCV000888903	uncertain significance	not provided	2023-02-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251164 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 32438681 (2020), 29161300 (2017), 27062684 (2016), and 26306726 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000077134	SCV001140540	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000218431	SCV001345620	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-31	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 1290 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in two suspected hereditary breast and ovarian cancer families (PMID: 27062684, 29161300) and an individual affected with ovarian cancer who also carried a BRCA2 copy number variant (PMID: 26306726, 32438681). This variant has been identified in 2/251164 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193691	SCV001362703	uncertain significance	not specified	2019-04-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3868A>G (p.Lys1290Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251164 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3868A>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Alemar_2017, Azzollini_2016, Minucci_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 exon 20 del (Minucci_2015)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193691	SCV002550987	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000218431	SCV003851057	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP)	RCV000077134	SCV000108931	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-09-07	no assertion criteria provided	clinical testing