ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4675G>A (p.Glu1559Lys) (rs80356988)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031185 SCV001161548 pathogenic Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.99607
Ambry Genetics RCV000131823 SCV000186878 pathogenic Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing The c.4675G>A pathogenic mutation (also known as ​p.E1559K), located in coding exon 13 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4675. 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 addition to potential splicing impact, this alteration changes the glutamate at codon 1559 to lysine, an amino acid with similar properties. In vitro transcript analyses showed that this alteration activated a cryptic splice site leading to the loss of the last 11 nucleotides of the exon and causing a premature stop codon (Ambry internal data; Wappenschmidt B et al. PLoS One. 2012;7(12):e50800). This mutation has been reported in a European individual diagnosed with ovarian cancer at age 50 who also had a family history of early onset breast/ovarian cancer, as well as in a Latvian individual diagnosed with both breast and ovarian cancer under the age of 50y (Wappenschmidt B et al. PLoS One. 2012;7(12):e50800; Tihomirova L et al. Adv Med Sci. 2014 Mar;59(1):114-9). Additionally, two women with this alteration who underwent prophylactic bilateral salpingo-oophorectomy were found to have incidental fallopian tube cancer (Callahan MJ et al. J Clin Oncol. 2007 Sep 1;25(25):3985-90; Conner JR et al. Gynecol Oncol. 2014 Feb;132(2):280-6). Based on the majority of evidence to-date, this alteration is interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031185 SCV000326020 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000482921 SCV000564744 likely pathogenic not provided 2015-02-28 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4675G>A at the cDNA level. Using alternate nomenclature, this variant has been previously published as BRCA1 4794G>A. Located in last nucleotide of exon 14, multiple splicing models predict that this variant destroys the natural splice donor site for intron 14 and causes abnormal splicing. BRCA1 c.4675G>A has been reported in at least three individuals with ovarian cancer (Wappenschmidt 2012, Janavicius 2014, Tihomirova 2014). In addition, RNA analysis suggested that this variant results in partial loss of the natural splice donor site and activation of a cryptic splice donor site (Wappenschmidt 2012). Although the nucleotide substitution results in the change of a Glutamic Acid to a Lysine at codon 1559, and is called Glu1559Lys in the literature, we are using only the nucleotide nomenclature to refer to the mutation since the defect is mainly due to abnormal splicing rather than a resulting missense pathogenic variant. BRCA1 c.4675G>A was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The nucleotide which is altered, a guanine (G) at base 4675, is conserved across species. Based on the current evidence, we consider this mutation to be a likely pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482921 SCV001133595 pathogenic not provided 2019-02-11 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Statistically enriched in patients. Predicted to have a tolerated effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000482921 SCV001449936 pathogenic not provided 2018-06-13 criteria provided, single submitter clinical testing
Invitae RCV000496604 SCV001584390 pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1559 of the BRCA1 protein (p.Glu1559Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant also falls at the last nucleotide of exon 14 of the BRCA1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families with breast and ovarian cancer (PMID: 23239986, 25066507, 24333842, 24797986, 17761984). This variant is also known as c.4794G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 37604). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant activates a cryptic splice site, leading to an aberrant transcript lacking the last 11 nucleotides of exon 14 (also known as exon 15) (PMID: 23239986, 31143303). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000496604 SCV001623417 pathogenic Hereditary breast and ovarian cancer syndrome 2021-05-07 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4675G>A (p.Glu1559Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. This sequence change occurs at the last nucleotide of exon 14. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. Consistent with these predications, a functional study report that this alteration activated a cryptic splice site resulting in the loss of the last 11 nucleotides of the exon 14 (Wappenschmidt_2012). The variant was absent in 251130 control chromosomes (gnomAD). c.4675G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. Six ClinVar submitters including an expert panel (ENIGMA) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031185 SCV000053785 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031185 SCV000145148 pathogenic Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496604 SCV000587416 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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