Submissions for variant NM_007294.4(BRCA1):c.4675G>C (p.Glu1559Gln)

dbSNP: rs80356988

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131825	SCV000186880	pathogenic	Hereditary cancer-predisposing syndrome	2020-07-05	criteria provided, single submitter	clinical testing	The c.4675G>C variant (also known as p.E1559Q) is located in coding exon 13 of the BRCA1 gene. This variant results from a G to C substitution at nucleotide position 4675. The glutamic acid at codon 1559 is replaced by glutamine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 13 which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA analysis showed that this alteration induces expression of a transcript lacking 11 nucleotides at the end of coding exon 13 (also called exon 15 in the literature-Ambry internal data; Davy G et al. Eur. J. Hum. Genet., 2017 10;25:1147-1154). Furthermore, a close match alteration at the same nucleotide position, BRCA1 c.4675G>A has been shown in multiple studies to have the same splice defect as this alteration (Wappenschmidt B et al. PLoS ONE, 2012 Dec; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14; Koczkowska M et al. Cancers (Basel), 2018 Nov;10: ). This alteration was functional in a protein assay (Woods NT et al. NPJ Genom Med, 2016 Mar;1) and is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031186	SCV000326021	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131825	SCV001340175	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 1559 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). This variant is located in the last nucleotide of exon 14 of the BRCA1 gene and splice site prediction tools suggest that this variant may impact RNA splicing. An RNA study has shown that this variant causes deletion of the last 11 nucleotides of exon 14 (also know as exon 15 in the literature) and skipping of exon 14 in the RNA transcripts (PMID: 28905878). Both aberrant transcripts are expected to result in an absent or non-functional protein product. This variant has been reported in an individual with personal and/or family history of breast and/or ovarian cancer (PMID: 27157322). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV001379224	SCV001576985	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-05-02	criteria provided, single submitter	clinical testing	This variant disrupts the c.4675 nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 23239986, 24333842, 25066507, 31143303). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. This sequence change affects codon 1559 of the BRCA1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA1 protein. This variant also falls at the last nucleotide of exon 14, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with personal and/or family history of hereditary breast and/or ovarian cancer (PMID: 28975465, 29446198). ClinVar contains an entry for this variant (Variation ID: 37605). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 28905878). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811228	SCV002050156	pathogenic	not provided	2021-03-24	criteria provided, single submitter	clinical testing	The BRCA1 c.4675G>C; p.Glu1559Gln variant (rs80356988) is reported in the literature in an individual affected with hereditary breast and ovarian cancer (HBOC) syndrome (Davy 2017). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant occurs in the last nucleotide of exon 15, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Consistent with these predictions, mRNA studies demonstrate that the variant leads to aberrant splicing, characterized by skipping of exon 15 or use of a cryptic splice donor 11 nucleotides upstream, both of which lead to frameshifts (Davy 2017). Another variant at the same nucleotide (c.4675G>A) also has been reported in HBOC patients and leads to aberrant splicing (Wangensteen 2019, Wappenschmidt 2012). Based on available information, the c.4675G>C variant is considered to be pathogenic. References: Davy G et al. Detecting splicing patterns in genes involved in hereditary breast and ovarian cancer. Eur J Hum Genet. 2017 Oct;25(10):1147-1154. PMID: 28905878. Wangensteen T et al. Diagnostic mRNA splicing assay for variants in BRCA1 and BRCA2 identified two novel pathogenic splicing aberrations. Hered Cancer Clin Pract. 2019 May 22;17:14. PMID: 31143303. Wappenschmidt B et al. Analysis of 30 putative BRCA1 splicing mutations in hereditary breast and ovarian cancer families identifies exonic splice site mutations that escape in silico prediction. PLoS One. 2012;7(12):e50800. PMID: 23239986.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000031186	SCV002072886	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing	The missense variant p.E1580Q in BRCA1 (NM_007300.4) has been previously reported as E1559Q in patients affected with breast cancer. Functional studies demonstarted a damaging effect (Davy G et al,2018). It has been submitted to ClinVar as Pathogenic. The p.E1580Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.E1580Q variant is predicted to disrupt splicing by all splice site algorithms. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001811228	SCV004219416	likely pathogenic	not provided	2016-06-29	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals and families with breast and/or ovarian cancer (PMIDs: 29446198 (2018), 28975465 (2017), 27157322 (2016)). Studies assessing BRCA1 mRNA splicing report the variant causes the skipping of exon 14 by deleting the last 11 nucleotides in the exon. This improper splicing is expected to result in frameshifts in the RNA transcripts and an absent or non-functional protein product (PMIDs: 28905878 (2017), 15235020 (2004)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031186	SCV000053786	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-09-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031186	SCV000145149	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Laboratoire de Biologie et Génétique du Cancer, Centre François Baclesse	RCV000031186	SCV000538190	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031186	SCV003927191	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	The c.4738G>C variant (also known as p.Glu1580Gln) is located in coding exon 13 of the BRCA1 gene. This variant results from a G to C substitution at nucleotide position 4738. The glutamic acid at codon 1580 is replaced by glutamine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 13 which makes it likely to have some effect on normal mRNA splicing. This alteration is predicted to decrease the efficiency of the native splice donor site by the BDGP and ESEfinder in silico models. RNA analysis showed that this alteration induces expression of a transcript lacking 11 nucleotides at the end of coding exon 13 (also called exon 15 in the literature-Davy G et al. Eur. J. Hum. Genet., 2017 10;25:1147-1154). Furthermore, a close match alteration at the same nucleotide position, BRCA1 c.4675G>A has been shown in multiple studies to have the same splice defect as this alteration (Wappenschmidt B et al. PLoS ONE, 2012 Dec; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14; Koczkowska M et al. Cancers (Basel), 2018 Nov;10: ). This alteration was functional in a protein assay (Woods NT et al. NPJ Genom Med, 2016 Mar;1) and is predicted to be tolerated by in silico analysis. ClinVar classifies this variant (37605) as pathogenic, rated 2 stars, with 6 submissions, 7 publications (15235020, 21394826, 23239986, 28781887, 28905878 and 2 more) and no conflicts. Therefore, this variant has been classified as pathogenic.
BRCAlab, Lund University	RCV000031186	SCV004243977	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing