ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4484G>A (p.Arg1495Lys) (rs80357389)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162878 SCV000213365 pathogenic Hereditary cancer-predisposing syndrome 2018-05-10 criteria provided, single submitter clinical testing The c.4484G>A pathogenic mutation (also known as p.R1495K), located in coding exon 12 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4484. The amino acid change results in arginine to lysine at codon 1495, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; and in one publication, RNA studies demonstrated that this mutation leads to skipping of exon 14 (coding exon 13) (Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38). In addition, this mutation has been observed in multiple breast and/or ovarian cancer cohorts (Lecarpentier J et al. Breast Cancer Res. 2012 Jul 3;14(4):R99; Alsop K et al. J. Clin. Oncol., 2012 Jul;30:2654-63; George J et al. Clin Cancer Res. 2013 Jul 1;19(13):3474-84; Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). Based on the available evidence, c.4484G>A is classified as a pathogenic mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031178 SCV000325977 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031178 SCV000487909 likely pathogenic Breast-ovarian cancer, familial 1 2015-12-10 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000031178 SCV000564372 pathogenic Breast-ovarian cancer, familial 1 2015-10-09 criteria provided, single submitter clinical testing
GeneDx RCV000479568 SCV000568404 pathogenic not provided 2017-06-29 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.4484G>A at the cDNA level. Using alternate nomenclature, this pathogenic variant would be defined as BRCA1 4603G>A. Located in the last nucleotide of exon 14, it disrupts a natural splice donor site and causes abnormal splicing. RNA analysis has demonstrated that BRCA1 c.4484G>A causes skipping of exon 14 (Houdayer 2012). Although the nucleotide substitution results in the change of an Arginine to a Lysine at codon 1495, and is called BRCA1 Arg1495Lys in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. BRCA1 c.4484G>A was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). The nucleotide which is altered, a guanine (G) at base 4484, is conserved across species. This variant has been observed in individuals with breast and/or ovarian cancer, as well as in individuals who underwent evaluation for hereditary breast and ovarian cancer (Judkins 2005, Alsop 2012, Lecarpentier 2012, George 2013, Fernandes 2016). Based on currently available evidence, we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479568 SCV000887697 likely pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162878 SCV000905202 pathogenic Hereditary cancer-predisposing syndrome 2018-02-06 criteria provided, single submitter clinical testing
Invitae RCV001389264 SCV001590561 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 1495 of the BRCA1 protein (p.Arg1495Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 13 of the BRCA1 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer (PMID: 22762150, 27741520) and ovarian cancer (PMID: 23633455, 22711857), as well as in a study associated with increased risk of breast and ovarian cancers (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 37597). Experimental studies evaluating the effect of this sequence change on RNA splicing have shown that this variant results in aberrant BRCA1 splicing, leading to the skipping of exon 14 (PMID: 22505045, 19471317). Two different missense substitutions affecting this nucleotide, c.4484G>C (p.Arg1495Thr) and c.4484G>T (p.Arg1495Met), have been determined to be pathogenic (Invitae). This suggests that this nucleotide is critical for BRCA1 function, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031178 SCV000053778 uncertain significance Breast-ovarian cancer, familial 1 2008-08-12 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031178 SCV000145099 pathogenic Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357179 SCV001552558 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing

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