Submissions for variant NM_007294.4(BRCA1):c.2834_2836delinsC (p.Ser945fs)

dbSNP: rs386134270

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)	RCV000077529	SCV000282292	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768645	SCV000219223	pathogenic	Breast and/or ovarian cancer	2022-10-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200323	SCV000255307	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser945Thrfs*6) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer from the French-Canadian population (PMID: 8933332, 16905680, 21324516, 23621881, 25884701). This variant is also known as 2953del3+C and 2953delGTAinsC. ClinVar contains an entry for this variant (Variation ID: 54694). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000077529	SCV000296486	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-06-10	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077529	SCV000325472	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000480902	SCV000566541	pathogenic	not provided	2020-08-10	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; Identified in patients with a personal or family history consistent with pathogenic variants in this gene, and is common in the French Canadian population (Durocher 1996, Tonin 1998, Oros 2004, Simard 2007, Ghadirian 2014); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2953_2955delGTAinsC; This variant is associated with the following publications: (PMID: 21947752, 8933332, 21324516, 25884701, 15382066, 16905680, 23621881, 9792861, 10422801, 23302520, 24950059, 26941049, 29907814, 30322717, 32300229, 32719484)
Department of Pathology and Molecular Medicine, Queen's University	RCV000200323	SCV000588042	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000583567	SCV000688402	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-21	criteria provided, single submitter	clinical testing	This variant replaces 3 nucleotides in exon 10 of the BRCA1 gene with 1 new nucleotide, 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 reported in individuals and families affected with breast and/or ovarian cancer, and is common in the French-Canadian population (PMID: 8933332, 9792861, 10686936, 15382066, 16905680, 21324516, 23621881, 24333842, 25884701). This variant has been identified in 24 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). In a large breast cancer case-control study, this variant has been observed in 0/60466 cases and 1/53460 controls (PMID: 33471991). 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.
Ambry Genetics	RCV000583567	SCV001177715	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-23	criteria provided, single submitter	clinical testing	The c.2834_2836delGTAinsC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from the deletion of 3 nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.S945Tfs*6). This alteration has been recognized as a founder mutation in the French Canadian population, having been identified in multiple individuals and families of French Canadian descent with hereditary breast and/or ovarian cancer (Durocher F et al. J Med Genet 1996 Oct;33(10):814-9; Tonin PN et al. Am J Hum Genet, 1998 Nov;63:1341-51; Oros KK et al. Int. J. Cancer 2004 Nov;112(3):411-9; Ghadirian P et al. Clin Genet 2014 Jan;85(1):31-5; Belanger MH et al. J Ovarian Res 2015;8(1):1). Of note, this alteration is also designated as 2953delGTAinsC in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200323	SCV001337805	pathogenic	Hereditary breast ovarian cancer syndrome	2020-01-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2834_2836delinsC (p.Ser945ThrfsX6) 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. The variant was absent in 251290 control chromosomes (gnomAD). c.2834_2836delinsC has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Durocher_1996, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Eight ClinVar submitters including an expert panel (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077529	SCV000109330	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-16	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077529	SCV000144558	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	RCV000200323	SCV000587256	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353734	SCV000591412	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Ser945ThrfsX6 variant was identified in 13 of 3714 proband chromosomes (frequency: 0.004) from individuals of French Canadian families with ovarian and breast cancer (Durocher 1996, Feilotter 2014, Letourneau 2012, Oros 2004, Simard 2007, Zhang 2011), however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified by our laboratory in 8 individuals with ovarian and breast cancer. The variant was also identified in the ClinVar database (classified as a Pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports), the BIC database (9X with clinical importance), and UMD (1X as a causal variant).The p.Ser945ThrfsX6 deletion/insertion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 945 and leads to a premature stop codon 6 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.