Submissions for variant NM_007294.4(BRCA1):c.2389_2390del (p.Glu797fs)

dbSNP: rs80357695

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083182	SCV000299757	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047820	SCV000075833	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.Glu797Thrfs*3) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 10634513, 25070656). It has also been observed to segregate with disease in related individuals. This variant is also known as 469C>T, Pro157Ser. ClinVar contains an entry for this variant (Variation ID: 54552). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162855	SCV000213342	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-21	criteria provided, single submitter	clinical testing	The c.2389_2390delGA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 2 nucleotides at positions 2389 and 2390, causing a translational frameshift with a predicted alternate stop codon (p.E797Tfs*3). Functional studies performed on breast tumor cells from a Japaense woman with this alteration demonstrated <20% BRCA1 protein expression (Yoshikawa K et al. Clin Cancer Res, 1999 Jun;5:1249-61). In a stop codon assay, 48% of the colonies containing c.2389_2390delGA exhibited growth failure, indicating loss of function (Sakayori M et al. J Hum Genet, 2003;48:130-7). This alteration has been identified in individuals who underwent clinical BRCA1/2 testing from various populations, as well as in ovarian cancer cohorts and in high risk breast cancer cohorts (de Souza Timoteo AR et al. Breast Cancer Res Treat, 2018 Dec;172:637-646; Palmero EI et al. Sci Rep, 2018 06;8:9188; Arai M et al. J Hum Genet, 2018 Apr;63:447-457; Kashima K et al. Jpn J Cancer Res, 2000 Apr;91:399-409; Alsop K et al. J Clin Oncol, 2012 Jul;30:2654-63; Yamashita Y et al. Breast Cancer Res. Treat., 1999 Nov;58:11-7; Luyeye Mvila G et al. BMC Public Health, 2014 Jul;14:759; Kawahara M et al. J Hum Genet, 2004 May;49:391-395; Donenberg T et al. Breast Cancer Res Treat, 2016 08;159:131-8). Of note, this alteration is also described as 2507delAG and 2508delGA in the literature. 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	RCV000083182	SCV000325339	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507145	SCV000600286	pathogenic	not provided	2016-09-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047820	SCV000918700	pathogenic	Hereditary breast ovarian cancer syndrome	2019-06-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2389_2390delGA (p.Glu797ThrfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250564 control chromosomes. c.2389_2390delGA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Yoshikawa_1999, Kawahara_2004, Kashima_2000, Alsop_2012, Luyeye Mvila_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000162855	SCV001340810	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-07	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2508delGA, 2507delAG and deletion of 2bp in codon 797 in BRCA1 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 10326698, 10634513, 10804288, 12624724, 15168169, 22711857, 25070656, 27469594). 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.
Baylor Genetics	RCV000083182	SCV004215193	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-03-10	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083182	SCV000115256	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083182	SCV000144401	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000083182	SCV002589096	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162403	SCV002758474	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research