Submissions for variant NM_007294.4(BRCA1):c.2989_2990dup (p.Asn997fs)

dbSNP: rs80357829

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000143831	SCV000299866	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	RCV000164310	SCV000214941	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-22	criteria provided, single submitter	clinical testing	The c.2989_2990dupAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of AA at nucleotide position 2989, causing a translational frameshift with a predicted alternate stop codon (p.N997Kfs*4). This mutation has been reported in several breast and/or ovarian cancer families in the literature (Peelen T, Am. J. Hum. Genet. 1997 May; 60(5):1041-9; Ligtenberg MJ, Br. J. Cancer 1999 Mar; 79(9-10):1475-8; Cunningham, JM et al. Sci Rep. 2014 Feb 7;4:4026; Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9; van Haaften C et al. Int. J. Gynecol. Cancer, 2017 Oct;27:1571-1578). This alteration is also referred to as c.2990_2991insAA and 3109insAA 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	RCV000237066	SCV000292515	pathogenic	not provided	2015-06-10	criteria provided, single submitter	clinical testing	This duplication of 2 nucleotides in BRCA1 is denoted c.2989_2990dupAA at the cDNA level and p.Asn997LysfsX4 (N997KfsX4) at the protein level. The normal sequence, with the bases that are duplicated in braces, is GAAA[AA]TCTG. The duplication causes a frameshift, which changes an Asparagine to a Lysine at codon 997, and creates a premature stop codon at position 4 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.2989_2990dupAA, also reported as BRCA1 c.2990_2991insAA, 3108insAA, 3108_3109dupAA, or 3109insAA using alternate nomenclature, has been reported in families with multiple cases of breast and/or ovarian cancer and individuals with epithelial ovarian or fallopian tube cancers (Peelen 1997, Norquist 2010, Song 2014, Cunningham 2014). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000143831	SCV000325516	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000143831	SCV000564359	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-03-30	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000143831	SCV000743409	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-10	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000143831	SCV000744642	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000143831	SCV000839897	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-05-25	criteria provided, single submitter	clinical testing	The c.2989_2990dup (p.Asn997Lysfs*4) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 9150151, 24504028]. This variant is considered a founder mutation among the Dutch and Belgium populations [PMID 9150151]. This 2 bp duplication in exon 10 results in a frameshift and the creation of a premature stop codon. This variant is thus predicted to result in a loss of function of the protein. This variant has not been detected in the ExAC database. This variant thus classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000164310	SCV000909327	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	This variant inserts 2 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 reported in individuals affected with ovarian cancer (PMID: 24728189, 24504028, 32199636), and has been identified in high risk breast and ovarian cancer families (PMID: 9150151, 10188893, 16287141, 16683254, 29339979). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496906	SCV001581144	pathogenic	Hereditary breast ovarian cancer syndrome	2024-07-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn997Lysfs*4) 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: 9150151, 16287141, 16683254, 24504028). This variant is also known as 3109insAA. ClinVar contains an entry for this variant (Variation ID: 54738). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496906	SCV002570844	pathogenic	Hereditary breast ovarian cancer syndrome	2022-07-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2989_2990dupAA (p.Asn997LysfsX4) 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 250578 control chromosomes (gnomAD). c.2989_2990dupAA (also known as c.2990_2991insAA) has been reported in the literature in multiple individuals affected with Hereditary Breast And/or Ovarian Cancer (examples: Rebbeck_2018 and Rush_2020) and the variant segregated with disease. These data indicate that the variant is very likely to be associated with disease. Ten submitters including an expert (ENIGMA) panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000237066	SCV004219332	pathogenic	not provided	2023-06-06	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 24728189 (2014), 24504028 (2014)) and endometrial cancer (PMID: 31492746 (2019)). The variant has also been observed in multiple individuals/families with hereditary breast and/or ovarian cancer (PMID: 9150151 (1997), 29339979 (2018), 16683254 (2006), 16287141 (2005)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000237066	SCV004242829	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803977	SCV004815621	pathogenic	BRCA1-related cancer predisposition	2024-09-03	criteria provided, single submitter	clinical testing	This variant inserts 2 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 reported in individuals affected with ovarian cancer (PMID: 24728189, 24504028, 32199636), and has been identified in high risk breast and ovarian cancer families (PMID: 9150151, 10188893, 16287141, 16683254, 29339979). 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	RCV000143831	SCV005058238	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-03-05	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000143831	SCV000053673	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-08-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000143831	SCV000144598	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496906	SCV000587268	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000143831	SCV000733632	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000237066	SCV001906368	pathogenic	not provided		no assertion criteria provided	clinical testing