Submissions for variant NM_007294.4(BRCA1):c.2685_2686del (p.Pro897fs)

dbSNP: rs80357636

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077525	SCV000299810	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	RCV000077525	SCV000325431	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000510104	SCV000607768	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-06	criteria provided, single submitter	clinical testing	The c.2685_2686delAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 2685 to 2686, causing a translational frameshift with a predicted alternate stop codon (p.P897Kfs*5). This mutation has been reported in multiple hereditary breast and/or ovarian cancer families and has been reported as a Dutch founder mutation (Peelen T et al. Am. J. Hum. Genet., 1997 May;60:1041-9; Garvin AM et al. J Med Genet, 1997 Dec;34:990-5; Vehmanen P et al. Hum Mol Genet, 1997 Dec;6:2309-15; Verhoog LC et al. Eur J Cancer, 2001 Nov;37:2082-90; Piek JM et al. Fam Cancer, 2003;2:73-8; van der Hout AH et al. Hum Mutat, 2006 Jul;27:654-66; Vos JR et al. Cancer Epidemiol Biomarkers Prev, 2014 Nov;23:2482-91; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Haer-Wigman L et al. Eur J Hum Genet, 2019 02;27:325-330; Deng H et al. Mol Genet Genomic Med, 2019 06;7:e672). Of note, this alteration is also designated as 2804delAA and 2804_2805delAA 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.
Counsyl	RCV000077525	SCV000677645	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000510104	SCV000683055	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-29	criteria provided, single submitter	clinical testing	This variant deletes 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals and families affected with breast, ovarian and fallopian tube cancer (PMID: 8807330, 9150151, 9361038, 9429140, 12354934, 14574155, 24285858) and has been reported as a Dutch founder mutation that is also common in Belgium (PMID: 9150151, 17591843, 23199084). This variant has been identified in 1/250904 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504509	SCV000698973	pathogenic	Hereditary breast ovarian cancer syndrome	2016-05-16	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2685_2686delAA (p.Pro897Lysfs) 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. Mutation taster predicts a damaging outcome for this variant. The variant is absent in 121354 control chromosomes while it was reported in several HBOC patients indicating a deleterious impact. The variant is most prevalent in patients of Dutch origin and is known as a Dutch founder mutation (Peelen_AJHG_1997). Multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000077525	SCV000743411	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	RCV000077525	SCV000744649	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV000504509	SCV001587212	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro897Lysfs*5) 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 present in population databases (rs80357636, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 9150151, 11597388, 16683254, 19949876, 24285858, 27767231). It is commonly reported in individuals of Dutch ancestry (PMID: 9150151, 11597388, 16683254). This variant is also known as 2804delAA. ClinVar contains an entry for this variant (Variation ID: 54646). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000077525	SCV004171172	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	not provided
Baylor Genetics	RCV000077525	SCV004217000	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-01-25	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077525	SCV000109326	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-07-31	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077525	SCV000144512	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000077525	SCV000189893	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353865	SCV000591405	pathogenic	not provided		no assertion criteria provided	clinical testing	The c.2685_2686delAA located within exon 11b of BRCA1 is a deletion type mutation, which is predicted to lead to frameshift and a premature stop codon at position Pro897LysX5, and therefore resulting in truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in familial breast cancer patients. In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077525	SCV000733637	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000077525	SCV000745680	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-03-18	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001353865	SCV001906157	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077525	SCV004244079	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing