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

dbSNP: rs80357389

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162878	SCV000213365	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-30	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. RNA studies demonstrated that this mutation leads to skipping of coding exon 12, which results in a transcript subject to nonsense-mediated mRNA decay (Ambry internal data; Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38). Another alteration impacting the same donor/acceptor site (c.4484G>T) has been shown to have a similar impact on splicing (Ambry internal data; Yang Y et al. Hum. Mol. Genet. 2003 Sep;12:2121-31; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38). This nucleotide position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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	RCV000031178	SCV000325977	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031178	SCV000487909	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-10	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031178	SCV000564372	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000479568	SCV000568404	pathogenic	not provided	2023-01-09	criteria provided, single submitter	clinical testing	RNA analyses demonstrate that this variant leads to skipping of exon 14, resulting in premature protein truncation, subject to nonsense-mediated decay (Houdayer et al., 2012; Wangensteen et al., 2019); Observed in individuals with breast and/or ovarian cancer (Alsop et al., 2012, George et al., 2013, Fernandes et al., 2016, Turner et al., 2018, Slavin et al., 2019); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4603G>A; This variant is associated with the following publications: (PMID: 22711857, 27741520, 28888541, 22762150, 19471317, 23633455, 22045683, 21523855, 15280182, 16267036, 28637432, 29339979, 28781887, 30728895, 29875428, 29446198, 30765603, 31143303, 31131967, 31911673, 31124283, Tan2020[Abstract], Lertwilaiwittaya2020[Case Report], 34981296, 35918668, 35665744, 15343273, 22737296, 22505045)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479568	SCV000887697	pathogenic	not provided	2022-11-09	criteria provided, single submitter	clinical testing	The variant occurs at the last base of an exon and interferes with normal BRCA1 mRNA splicing. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with breast/ovarian cancer (PMID: 22711857 (2012), 23633455 (2013), 27741520 (2016), 28637432 (2017), 29875428 (2018), 34196900 (2021)). In vitro studies have shown that this variant causes a severe and complete splicing defect resulting in exon 13 (legacy exon 14) skipping (PMID: 19471317 (2009), 22505045 (2012), 31143303 (2019)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000162878	SCV000905202	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 1495 of the BRCA1 protein and alters the conserved guanine nucleotide immediately adjacent to the intron 13 splice donor site. RNA studies have shown that this variant resulted in the out-of-frame skipping of exon 13 and that this variant transcript is not stably expressed based on an allelic imbalance assay on patient-derived RNA (PMID: 19471317, 22505045, 31143303). This variant has been reported in at least three individuals affected with breast and ovarian cancer (PMID: 22711857, 27741520, 28637432) and also in suspected hereditary breast and ovarian cancer families (PMID: 22505045, 22762150). Two similar variants at this nucleotide position, c.4484G>T and c.4484G>C, have been reported in individuals and families affected with breast and ovarian cancer (PMID: 10571952, 21120943, 22762150, 24607278, 27425403) and shown by RNA analysis to cause out-of-frame skipping of exon 13 (PMID: 10571952, 12915465, 21120943, 22505045, 24607278). 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 Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389264	SCV001590561	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1495 of the BRCA1 protein (p.Arg1495Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 22711857, 22762150, 23633455, 27741520, 29446198). ClinVar contains an entry for this variant (Variation ID: 37597). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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 missense change results in skipping of exon 13 (also called exon 14 in published literature) and introduces a premature termination codon (PMID: 19471317, 22505045; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.4484G nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001389264	SCV002598861	pathogenic	Hereditary breast ovarian cancer syndrome	2022-09-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4484G>A (p.Arg1495Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a canonical 5' splicing donor site and two predict the variant weakens the 5' donor site. At least two publications have provided experimental evidence to demonstrate that this variant does indeed affect mRNA splicing, indicating that it results in the skipping of exon 13 which produces a frameshift, ultimately leading to a premature stop codon (e.g. Houdayer_2012, Wangensteen_2019). The variant was absent in 251172 control chromosomes (gnomAD). c.4484G>A has been reported in the literature in multiple individuals affected with breast/ovarian cancer, including those with a family history of breast/ovarian cancer (e.g. Lecarpentier_2012, Alsop_2012, Fernandes_2016, Turner_2019, Ren_2021, Solano_2021). These data strongly suggest that the variant is associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=6) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000031178	SCV004216921	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-24	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031178	SCV000053778	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2008-08-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031178	SCV000145099	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000479568	SCV001977635	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000479568	SCV001978573	uncertain significance	not provided		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250476	SCV002520835	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000031178	SCV004243987	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing