Submissions for variant NM_007294.4(BRCA1):c.3477_3480del (p.Ile1159fs)

dbSNP: rs80357781

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077550	SCV000299950	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.
Invitae	RCV000048209	SCV000076222	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile1159Metfs*50) 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 (rs80357781, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 8968102, 10612800, 12872265, 17018160, 26187060). This variant is also known as 3596delAAAG and 3596del4. ClinVar contains an entry for this variant (Variation ID: 54896). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000215402	SCV000275708	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-20	criteria provided, single submitter	clinical testing	The c.3477_3480delAAAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides between nucleotide positions 3477 and 3480, causing a translational frameshift with a predicted alternate stop codon (p.I1159Mfs*50). This mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer, and also in an individual with pancreatic cancer (Montagna M et al. Cancer Res. 1996 Dec;56(23):5466-9; Saxena S et al. BMC Med. Genet. 2006 Oct;7:75; Johns AL et al. Genome Med. 2017 04;9(1):41; Kwong A et al. J. Med. Genet. 2016 Jan;53:15-23; Marchetti C et al. Ann. Surg. Oncol. 2018 Nov;25:3701-3708). One proband with this mutation reportedly also carried a mutation in BRCA2 (Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18(1):112). This alteration was 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 designated as 3596del4 in the 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	RCV000235430	SCV000293467	pathogenic	not provided	2018-12-11	criteria provided, single submitter	clinical testing	This deletion of 4 nucleotides in BRCA1 is denoted c.3477_3480delAAAG at the cDNA level and p.Ile1159MetfsX50 (I1159MfsX50) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAAT[delAAAG]GAAG. The deletion causes a frameshift, which changes an Isoleucine to a Methionine at codon 1159, and creates a premature stop codon at position 50 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.3477_3480delAAAG, also published as 3596delAAAG and 3596del4 using alternate nomenclature, has been observed in association with breast and ovarian cancer (Montagna 1996, Stuppia 2003, Cortesi 2000, Saxena 2006). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077550	SCV000325662	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000048209	SCV000839255	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048209	SCV000916712	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3477_3480delAAAG (p.Ile1159MetfsX50) 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 allele was found at a frequency of 4e-06 in 251298 control chromosomes. c.3477_3480delAAAG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Arteni_2003, Judkins_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000215402	SCV001339913	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	clinical testing	This variant deletes 4 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 at least 7 individuals affected with breast and ovarian cancer (PMID: 8968102, 10612800, 12872265, 17018160, 26187060, 30128899; Color internal data; doi:10.5505/aot.2021.25348). This variant has been identified in 1/251298 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.
Baylor Genetics	RCV000077550	SCV004216889	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-11-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235430	SCV004219357	pathogenic	not provided	2023-01-12	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/251298 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 34026625 (2021), 33558524 (2021), 32341426 (2020), 30606148 (2019), 31528241 (2019), 30128899 (2018), 30078507 (2018), 27836010 (2016), and 26187060 (2016)). Based on the available information, this variant is classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077550	SCV000109351	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-01-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077550	SCV000144772	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Center of Medical Genetics and Primary Health Care	RCV000048209	SCV000987233	pathogenic	Hereditary breast ovarian cancer syndrome	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria The BRCA1 p.Ile1159Metfs variant is a known pathogenic variant also in exon 11 in a non-functional domain just before the BRSTCANCERI domain (S1180-1200Q aa) (PMID: 10198641) and in a mutational hotspot with 35 pathogenic variants (PM1 Pathogenic Moderate). The deletion causes a frameshift, which changes an Isoleucine to a Methionine at codon 1159, and creates a premature stop codon at position 50 of the new reading frame. This null variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). The allele frequency in GnomAD exomes is 0.00000398 which is less the threshold 0.0001 for recessive gene BRCA1, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000299950.2) (PP5 Pathogenic Supporting). 1 pathogenic prediction from GERP versus no benign prediction supports its deleterious effect (PP3 Pathogenic Supporting). In this study the variant p.Ile1159Metfs was found in 4 patients from two families - a sister/sister and a brother/sister pair (PP1 Pathogenic Supporting). The two sisters were 31 and 32 years old and the brother/sister pair were 57 and 54, respectively; all had unilateral breast cancer. Therefore, this variant was classified as a Pathogenic.