Submissions for variant NM_007294.4(BRCA1):c.2766del (p.Val923fs)

dbSNP: rs80357812

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083189	SCV000299831	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	RCV000047965	SCV000075978	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val923Leufs*77) 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 cancer (PMID: 10951344, 22333603, 26221963). ClinVar contains an entry for this variant (Variation ID: 54677). For these reasons, this variant has been classified as Pathogenic.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000083189	SCV000195911	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000213211	SCV000275639	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-29	criteria provided, single submitter	clinical testing	The c.2766delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2766, causing a translational frameshift with a predicted alternate stop codon (p.V923Lfs*77). This mutation has been detected in several patients, particularly of South Asian ancestry, with early-onset and/or triple-negative breast cancer (Ho GH et al. Cancer. 2000 Aug;89:811-6; Liede A et al. Am. J. Hum. Genet. 2002 Sep;71:595-606; Robertson L et al. Br J Cancer. 2012 Mar 13;106(6):1234-8; Donenberg T et al. Breast Cancer Res Treat. 2016 Aug;159(1):131-8). Of note, this mutation is also designated as 2885delA in published 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.
GeneDx	RCV000236621	SCV000293469	pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2885delA; This variant is associated with the following publications: (PMID: 10951344, 26221963, 24578176, 27469594, 22333603, 21702907, 12181777, 12188064, 26315209, 20104584, 34657373, 33646313, 12442265, 29470806, 29446198, 31853058)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083189	SCV000325460	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213211	SCV000683061	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide 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 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000083189	SCV000744646	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000213211	SCV002538156	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	curation
Baylor Genetics	RCV000083189	SCV004211746	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-07-29	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083189	SCV000115263	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083189	SCV000144541	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-06-22	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000083189	SCV000591410	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The BRCA1 p.Val923LeufsX77 variant was identified in 1 of 86 proband chromosomes (frequency: 0.012) from Singaporean individuals or families with early onset breast cancer and was not identified in 100 control chromosomes from healthy individuals (Ho 2000). The variant was also identified in dbSNP (ID: rs80357812) “With Pathogenic allele”, HGMD, the BIC database (1X with pathogenic clinical importance), and UMD (1X as a causal variant). The variant was identified in the ClinVar database with multiple submissions: Sharing Clinical Reports Project (SCRP) (derived from Myriad reports) as pathogenic, BIC as pathogenic, and INVITAE with classification not provided. The p.Val923LeufsX77 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 923 and leads to a premature stop codon 77 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000083189	SCV000733635	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing