Submissions for variant NM_007294.4(BRCA1):c.5335del (p.Gln1779fs)

dbSNP: rs80357590

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)	RCV000031238	SCV000300241	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	RCV000048947	SCV000076960	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1779Asnfs*14) 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 ovarian cancer (PMID: 11920621, 21324516, 26187060). This variant is also known as 5454delC. ClinVar contains an entry for this variant (Variation ID: 37657). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129334	SCV000184097	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-15	criteria provided, single submitter	clinical testing	The c.5335delC pathogenic mutation, located in coding exon 20 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 5335, causing a translational frameshift with a predicted alternate stop codon (p.Q1779Nfs*14). This mutation has been reported in multiple breast and ovarian cancer patients (De Leon Matsuda ML et al. Int. J. Cancer. 2002 Apr;98:596-603; Kuo WH et al. J. Hum. Genet. 2012 Feb;57:130-8; Ibrahim SS et al. J. Exp. Clin. Cancer Res. 2010 Jun;29:82; Yang XR et al. Breast Cancer Res.Treat. 2017 Oct;165:687-697; Kwong A et al. Hong Kong Med J. 2018 06;24 Suppl 3(3):4-6). Of note, this alteration is also designated as 5454delC 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	RCV000159930	SCV000210057	pathogenic	not provided	2023-02-02	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; Published functional studies demonstrate a significant decrease of HDR activity (Lu et al., 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5454delC; This variant is associated with the following publications: (PMID: 30702160, 29452958, 32856862, 11920621, 25814778, 21324516, 22277901, 20579331, 28918466, 26187060, 17591843, 16267036, 28664506, 29487695, 29937436, 29128982, 29625052, 31825140, 30787465, 31892343, 20104584, 35205313, 26689913)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031238	SCV000326282	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048947	SCV000699245	pathogenic	Hereditary breast ovarian cancer syndrome	2016-06-06	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.5335delC (p.Gln1779Asnfs) 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.5387C>A, p.Ser1796X; c.5417delC, p.Pro1806fs). One in silico tool predicts a damaging outcome for this variant and this variant is absent in 121004 control chromosomes. The variant has been reported in numerous patients in the literature and databases, and has been reported as a Filipino founder mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159930	SCV000887723	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 multiple individuals with breast or ovarian cancer (PMIDs: 32856862 (2020), 29937436 (2018), 28664506 (2017), 22277901 (2012), 20579331 (2012), 21324516 (2011), 11920621 (2002)). The frequency of this variant in the general population, 0.000004 (1/251422 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Genome-Nilou Lab	RCV000031238	SCV001745219	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-07-04	criteria provided, single submitter	clinical testing	we found this variant in a 55-year-old female with unilateral breast cancer (Ductal Carcinoma). she has history of colorectal cancer in her first degree relatives (her mother).
Baylor Genetics	RCV000031238	SCV004216852	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-01-17	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031238	SCV000053842	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-07-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031238	SCV000145468	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	RCV000048947	SCV000587498	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353970	SCV000591617	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Gln1779AsnfsX14 variant has been reported in the literature in at least 3/1352 proband chromosomes from individuals with hereditary breast and/or ovarian cancer; although no control chromosomes were tested in these particular studies to establish its frequency in the general population (Selected publications: Kuo 2012; Matsuda 2002; Ferla 2007). Of particular interest is the finding that this variant is reported as a founder mutation in Malay and Philippine breast cancer patients (Ferla 2007), and that the ethnic background of this individual is Filipino. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1779 and leads to a premature stop codon 14 codons downstream. This alteration is predicted to lead to a truncated or absent protein and loss of function. Loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast cancer patients. In summary, based on the above information, this variant is classified as Pathogenic.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031238	SCV003927199	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	A pathogenic variant was detected in this sample .This sequence change creates a premature translational stop signal (p.Gln1800fs) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 11920621, 21324516, 26187060). This variant is also known as 5398delC. ClinVar contains an entry for this variant (Variation ID: 37657). For these reasons, this variant has been classified as Pathogenic. This variant was confirmed by Sanger Sequencing. Genetics counseling is recommended
BRCAlab, Lund University	RCV000031238	SCV004243919	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing