Submissions for variant NM_007294.4(BRCA1):c.2940del (p.Pro981fs)

dbSNP: rs80357876

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)	RCV000077120	SCV000299860	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.
Ambry Genetics	RCV000130182	SCV000185019	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-28	criteria provided, single submitter	clinical testing	The c.2940delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2940, causing a translational frameshift with a predicted alternate stop codon (p.P981Hfs*19). In one study, this alteration was identified in an individual with serous ovarian cancer (Pennington KP et al. Clin. Cancer Res. 2014 Feb;20(3):764-75). In a case control study, this alteration was detected in 1/2222 individuals with invasive epithelial ovarian cancer and 0/1528 matched controls. (Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Of note, this alteration is also known as 3059delA 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.
Invitae	RCV000206597	SCV000261453	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro981Hisfs*19) 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 epithelial ovarian cancer (PMID: 24728189). This variant is also known as 3059delA. ClinVar contains an entry for this variant (Variation ID: 91603). For these reasons, this variant has been classified as Pathogenic.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077120	SCV000267704	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000236676	SCV000292897	pathogenic	not provided	2023-05-12	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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Pennington et al., 2014; Song et al., 2014; Lilyquist et al., 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3059delA; This variant is associated with the following publications: (PMID: 16267036, 24240112, 24728189, 28152038, 31853058, 29446198, 20104584, 28888541)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077120	SCV000325502	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236676	SCV000600308	pathogenic	not provided	2017-05-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000206597	SCV000698990	pathogenic	Hereditary breast ovarian cancer syndrome	2016-08-02	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2940delA (p.Pro981Hisfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g.c.3764dupA/p.Asn1255fs). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in numerous HBOC patients and is absent in 124124 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999890	SCV000885075	pathogenic	not specified	2018-07-02	criteria provided, single submitter	clinical testing	The BRCA1 c.2940delA; p.Pro981fs variant (rs80357876), is reported in the literature in an individual with ovarian cancer (Song 2014), and reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 91603). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Song H et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014 Sep 1;23(17):4703-9.
Color Diagnostics, LLC DBA Color Health	RCV000130182	SCV000903721	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-13	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 been reported in two individuals affected with ovarian cancer (PMID: 24240112, 24728189) and has been identified in 2 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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.
Revvity Omics, Revvity	RCV000236676	SCV003812376	pathogenic	not provided	2022-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077120	SCV004212716	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-16	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077120	SCV000108917	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-12-21	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077120	SCV000144590	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing