Submissions for variant NM_007294.4(BRCA1):c.1333G>C (p.Glu445Gln)

gnomAD frequency: 0.00001  dbSNP: rs80356915

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129529	SCV000184305	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-30	criteria provided, single submitter	clinical testing	The p.E445Q variant (also known as c.1333G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 1333. The glutamic acid at codon 445 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Abdel-Razeq H et al. BMC Cancer, 2018 02;18:152; Machackova E et al. Klin Onkol, 2019;32:51-71; Rizzolo P et al. Int J Cancer, 2019 Jul;145:390-400; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). This alteration has also been reported in a low grade glioma patient from from The Cancer Genome Atlas (TCGA) (Huang KL et al. Cell, 2018 04;173:355-370.e14). In another study, this variant was reported in 0/60,466 breast cancer cases and in 2/53,461 healthy controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In addition, this alteration was functional in a homology directed DNA repair (HDR) assay (Lu C et al. Nat Commun, 2015 Dec;6:10086). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000347705	SCV000329119	uncertain significance	not provided	2020-09-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 1452G>C; This variant is associated with the following publications: (PMID: 20858050, 31409081, 16518693, 16267036, 23704879, 15385441, 26689913, 27062684, 29409476, 29684080, 28529006, 32546644, 29625052)
Color Diagnostics, LLC DBA Color Health	RCV000129529	SCV000682949	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 445 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has been reported that this variant does not impact BRCA1 function in a homology-directed repair assay (PMID: 26689913). This variant has been reported in at least four individuals affected with breast cancer and in suspected hereditary breast and ovarian cancer families (PMID: 26689913, 27062684, 294094760, 30613976, 31409081), and in a breast cancer case-control meta-analysis in 2/53459 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000141). This variant also has been reported in an individual affected with oligodendroglioma (PMID: 29625052) and in two individuals affected with Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (PMID: 29684080). This variant has been identified in 7/250918 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000347705	SCV000888843	uncertain significance	not provided	2020-12-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192442	SCV001360561	uncertain significance	not specified	2023-03-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1333G>C (p.Glu445Gln) results in a conservative amino acid change located in the BRCA1, serine-rich domain (IPR025994) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250918 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1333G>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example: Abdel-Razeq_2018, Azzollini_2016, Coulet_2010, Judkins_2005, Machackova_2019, Rizzolo_2019). At-least one report of this variant co-occurring with a pathogenic variant (c.2062C>T, p.Gln688*) in the PTCH1 gene as an alternate molecular basis of disease in an individual with Gorlin syndrome has been reported (Paulo_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had comparable homology-directed repair (HDR) activity to the wild type (example: Lu_2015 and Bouwman_2020). Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae	RCV000709488	SCV001494698	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 445 of the BRCA1 protein (p.Glu445Gln). This variant is present in population databases (rs80356915, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, male breast cancer, and/or ovarian cancer (PMID: 26689913, 27062684, 29409476, 29625052, 30613976, 34981296). ClinVar contains an entry for this variant (Variation ID: 54203). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 26689913, 32546644). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129529	SCV003846006	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).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001192442	SCV004026800	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000111589	SCV004818342	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 445 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has been reported that this variant does not impact BRCA1 function in a homology-directed repair assay (PMID: 26689913). This variant has been reported in at least four individuals affected with breast cancer and in suspected hereditary breast and ovarian cancer families (PMID: 26689913, 27062684, 29409476, 30613976, 31409081), and in a breast cancer case-control meta-analysis in 2/53459 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000141). This variant also has been reported in an individual affected with oligodendroglioma (PMID: 29625052) and in two individuals affected with Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (PMID: 29684080). This variant has been identified in 7/250918 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111589	SCV000144059	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000111589	SCV003927212	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	The p.E445Q variant (also known as c.1333G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 1333. The glutamic acid at codon 445 is replaced by glutamine, an amino acid with highly similar properties. One study showed that this variant performed similarly to the wildtype in a homology-directed repair assay (Lu C et al. Nat Commun. 2015 Dec;6:10086). This alteration has been reported as a variant of unknown significance some published studies; however, no clinical or other supporting information is provided (Judkins T et al. Cancer Res. 2005 Nov;65:10096-103; Coulet F et al. Genet Test Mol Biomarkers. 2010 Oct;14:677-90). This variant has also been reported in 1/1854 hereditary breast and/or ovarian cancer families (Azzollini J Eur. J. Intern. Med. 2016 Jul;32:65-71). This amino acid position is poorly conserved in available vertebrate species. In addition, in silico analysis showed benign computational verdict based on 8 benign predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, MVP and 3 more vs 5 pathogenic predictions from DEOGEN2, LIST-S2, M-CAP, MutationAssessor and SIFT and the position is not strongly conserved (GERP++ rejected substitutions = 0.761 is less than 5.5). This variant has an entry in ClinVar with 8 submissions all of which list it as uncertain significance. Therefore, this variant is classified as uncertain significance.
Department of Medical and Surgical Sciences, University of Bologna	RCV000111589	SCV004228328	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BS3(Strong)+BP1(Strong)+BP5(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)