Submissions for variant NM_007294.4(BRCA1):c.390C>A (p.Tyr130Ter)

dbSNP: rs80356888

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112439	SCV000299448	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000048376	SCV000076389	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr130*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80356888, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 16287141, 19656164, 22382806, 25834617). This variant is also known as 509C>A. ClinVar contains an entry for this variant (Variation ID: 55046). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131881	SCV000186936	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	The p.Y130* pathogenic mutation (also known as c.390C>A), located in coding exon 5 of the BRCA1 gene, results from a C to A substitution at nucleotide position 390. This changes the amino acid from a tyrosine to a stop codon within coding exon 5. This alteration has been reported in multiple families with breast and/or ovarian cancer (Kroiss R et al. Hum. Mutat., 2005 Dec;26:583-9; Sugano K et al. Cancer Sci., 2008 Oct;99:1967-76; Seong MW et al. Clin. Genet., 2009 Aug;76:152-60; Kim H et al. Breast Cancer Res. Treat., 2012 Aug;134:1315-26; Son BH et al. Breast Cancer Res. Treat., 2012 Jun;133:1143-52; Jeon YW et al. J Breast Cancer, 2015 Mar;18:97-100; Eoh KJ et al. Cancer Res Treat, 2018 Jul;50:917-925; Lilyquist J et al. Gynecol. Oncol., 2017 11;147:375-380; Choi MC et al. Int. J. Gynecol. Cancer, 2018 02;28:308-315; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). This alteration is also described in the literature as 509C>A. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112439	SCV000325785	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000112439	SCV000677636	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-02-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131881	SCV001351494	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 6 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/251444 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001353908	SCV002046567	pathogenic	not provided	2021-01-07	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMIDs: 16287141 (2005), 29020732 (2018), 30287823 (2018), 30309222 (2019), and 30350268 (2019)). The frequency of this variant in the general population is consistent with pathogenicity. This variant has been shown to be damaging to protein function relevant to disease mechanism (PMID: 25823446). Therefore, the variant is classified as pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001353908	SCV004026820	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112439	SCV000145229	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048376	SCV000587049	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353908	SCV000591261	pathogenic	not provided		no assertion criteria provided	clinical testing