Submissions for variant NM_007294.4(BRCA1):c.1380dup (p.Phe461fs)

dbSNP: rs80357714

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000030988	SCV000299589	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047447	SCV000075460	pathogenic	Hereditary breast ovarian cancer syndrome	2020-10-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe461Ilefs*19) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast cancer (PMID: 8808710, 23199084 24884479). This variant is also known as 1499insA in the literature. ClinVar contains an entry for this variant (Variation ID: 54226). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000214909	SCV000278204	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-04	criteria provided, single submitter	clinical testing	The c.1380dupA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of A at nucleotide position 1380, causing a translational frameshift with a predicted alternate stop codon (p.F461Ifs*19). This mutation has been reported in multiple hereditary breast and/or ovarian cancer (HBOC) families, and is noted to be a founder mutation in Italian populations (Caligo MA et al. Oncogene, 1996 Oct;13:1483-8; Aretini P et al. Breast Cancer Res Treat, 2003 Sep;81:71-9; Judkins T et al. Cancer Res, 2005 Nov;65:10096-103; Veschi S et al. Ann Oncol, 2007 Jun;18 Suppl 6:vi86-92; Musolino A et al. Breast, 2007 Jun;16:280-92; Marroni F et al. Ann. Hum. Genet., 2008 May;72:310-8; Palomba G et al. BMC Cancer, 2009 Jul;9:245; Janaviius R. EPMA J, 2010 Sep;1:397-412; Silva FC et al. BMC Med Genet, 2014 May;15:55; Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Palmero EI et al. Sci Rep, 2018 06;8:9188; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Toss A et al. Cancers (Basel), 2019 Feb;11:). Of note, this alteration is also designated as 1499insA 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000030988	SCV000325053	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000413703	SCV000492457	pathogenic	Breast neoplasm		criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047447	SCV000698855	pathogenic	Hereditary breast ovarian cancer syndrome	2016-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000657162	SCV000778880	pathogenic	not provided	2018-04-30	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in BRCA1 is denoted c.1380dupA at the cDNA level and p.Phe461IlefsX19 (F461IfsX19) at the protein level. The normal sequence, with the base that is duplicated in brackets, is AAAT[dupA]TTTG. The duplication causes a frameshift which changes a Phenylalanine to an Isoleucine at codon 461, and creates a premature stop codon at position 19 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.1380dupA, also reported as BRCA1 1499dupA, 1499insA, or c.1377_1378insA using alternate nomenclature, has been reported in association with Hereditary Breast and Ovarian Cancer and is a pathogenic founder variant in Italian populations (Stuppia 2003, Marroni 2008, Janavicius 2010, Pellegrino 2016). We consider this variant to be pathogenic.
Mendelics	RCV000030988	SCV001140607	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214909	SCV001360140	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-28	criteria provided, single submitter	clinical testing	This variant inserts 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 at least 14 families affected with hereditary breast and ovarian cancer and is thought to be a founder mutation in Italian population (PMID: 23199084). 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.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000030988	SCV001499622	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000030988	SCV004216899	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-10-12	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000030988	SCV000053580	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2009-11-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000030988	SCV000144070	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	RCV000047447	SCV000587125	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000030988	SCV004244129	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing