Submissions for variant NM_007294.4(BRCA1):c.3342_3345del (p.Glu1114_Glu1115insTer)

dbSNP: rs397509058

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077543	SCV000299927	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077543	SCV000325625	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077543	SCV000488951	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-08-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000521138	SCV000617452	pathogenic	not provided	2017-09-28	criteria provided, single submitter	clinical testing	This deletion of four nucleotides is denoted BRCA1 c.3342_3345delAGAA at the cDNA level and p.Glu1115Ter (E1115X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 3461_3464delAGAA. The normal sequence, with the bases that are deleted in brackets, is ATGA[delAGAA]GTAG. The deletion creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.3342_3345delAGAA has been observed in at least two individuals with breast and/or ovarian cancer and has been described as a recurrent variant in southern China (Kwong 2009, Kwong 2012). This variant is considered pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496369	SCV000699021	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3342_3345delAGAA (p.Glu1115X) 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 250250 control chromosomes. c.3342_3345delAGAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000776478	SCV000912040	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals affected with hereditary breast and ovarian cancer (PMID: 29487695, 30702160). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000521138	SCV001133549	pathogenic	not provided	2019-07-30	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Ambry Genetics	RCV000776478	SCV001181468	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-08	criteria provided, single submitter	clinical testing	The c.3342_3345delAGAA pathogenic mutation (also known as p.E1115*), located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 3342 to 3345. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been recognized in individuals of Chinese descent with breast and/or ovarian cancer (Kwong A et al. PLoS ONE. 2012 Sep;7(9); Karami F and Mehdipour P. Biomed. Res. Int. 2013 Nov;2013:928562). 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.
Invitae	RCV000496369	SCV001585111	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1115*) 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/or ovarian cancer (PMID: 16528604, 19353265, 22970155). This variant is also known as c.3450del4. ClinVar contains an entry for this variant (Variation ID: 54850). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149704	SCV003838902	pathogenic	Breast and/or ovarian cancer	2021-07-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077543	SCV004211767	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-03-23	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077543	SCV000109344	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-12-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077543	SCV000144729	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2013-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496369	SCV000587303	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000077543	SCV004244051	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing