Submissions for variant NM_007294.4(BRCA1):c.514del (p.Gln172fs)

gnomAD frequency: 0.00001  dbSNP: rs80357872

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083216	SCV000282337	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000048817	SCV000076830	pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55421). This variant is also known as 633delC. This premature translational stop signal has been observed in individual(s) with breast, ovarian and pancreatic cancer (PMID: 10528853, 17591842, 21989927, 25682074, 26219728). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln172Asnfs*62) 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).
Ambry Genetics	RCV000130785	SCV000185678	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-15	criteria provided, single submitter	clinical testing	The c.514delC pathogenic mutation, located in coding exon 6 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 514, causing a translational frameshift with a predicted alternate stop codon (p.Q172Nfs*62). This mutation has been reported in multiple individuals and families affected with hereditary breast and ovarian cancer (HBOC) syndrome (van Orsouw NJ et al. J Med Genet. 1999 Oct;36(10):747-53; Nedelcu R et al. Eur. J. Hum. Genet. 2002 Feb;10(2):150-2; Nanda R et al. JAMA 2005 Oct;294(15):1925-33; Russo A et al. Breast Cancer Res. Treat. 2007 Nov;105(3):267-76; Tai YC et al. J Natl Cancer Inst. 2007 Dec;99(23):1811-4; Miolo G et al. BMC Cancer 2009 Oct;9:360; Ghiorzo P et al. Fam Cancer. 2012 Mar;11(1):41-7; Incorvaia L et al. Cancers (Basel), 2020 May;12; Fanale D et al. Cancers (Basel), 2020 Aug;12). Of note, this alteration is also designated as 633delC 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	RCV000212158	SCV000210002	pathogenic	not provided	2023-07-25	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; Observed in several Hereditary Breast and Ovarian Cancer families (van Orsouw et al., 1999; Tai et al., 2007; Ghiorzo et al., 2012; Finch et al., 2015; Incorvaia et al., 2020); 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 633delC; This variant is associated with the following publications: (PMID: 27157322, 26219728, 25682074, 17591842, 20682393, 32438681, 28888541, 10528853, 18042939, 17221156, 27376475, 27566247, 21989927, 30128899, 29922827, 29907814, 29337092, 29625052, 26689913, 32854451, 30787465, 36139606, 34178674, 33573335, 32380732)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212158	SCV000296357	pathogenic	not provided	2015-07-03	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083216	SCV000326170	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130785	SCV000910961	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 7 of the BRCA1 gene, creating a frameshift and premature translation stop signal. It is also known as 633delC according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals with breast and/or ovarian cancer (PMID: 10528853, 17221156, 17591842, 25682074, 26219728) and pancreatic cancer (PMID: 21989927). This variant has been identified in 1/251472 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	RCV000048817	SCV000916783	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.514delC (p.Gln172AsnfsX62) 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. The variant allele was found at a frequency of 8.2e-06 in 121410 control chromosomes (ExAC). The variant, c.514delC, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Azzollini_2016, Wong-Brown_2015, Tai_2007). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000083216	SCV002761801	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-04-26	criteria provided, single submitter	clinical testing	The BRCA1 c.514delC variant is classified as Pathogenic (PVS1, PM2_Supporting, PP5) This BRCA1 c.514delC variant is located in exon Missing Exon and is predicted to cause a shift in the reading frame at codon 172. This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs80357872) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 55421). It has not been reported in HGMD. literature: Finch et al., 2016, PMID:26219728, Wong-Brown et al., 2015, PMID:25682074, Ghiorzo et al., 2012, PMID:21989927, Miolo et al., 2009, PMID:19818148, Tai et al., 2007, PMID:18042939, Russo et al., 2007, PMID:17221156, Nanda et al., 2005, PMID:16234499, van Orsouw et al., 1999, PMID:10528853, Azzollini et al., 2016, PMID:27062684, Nedelcu et al., 2002, PMID:11938448, Lu et al., 2015, PMID:26689913, Huang et al., 2018, PMID:29625052, Fanale et al., 2020, PMID:32854451
Revvity Omics, Revvity	RCV000212158	SCV003809202	pathogenic	not provided	2022-05-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000083216	SCV004215097	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-09	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083216	SCV000115290	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2009-11-23	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083216	SCV000145606	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-12-30	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048817	SCV000587058	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000083216	SCV000591275	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The p.Gln172AsnfsX62 deletion variant has been previously reported in the literature in at least 2 of 178 proband chromosomes in individuals or families with pancreatic and breast cancer (Ghiorzo 2012, van Orsouw 1999). The variant was also reported in HGMD, the UMD (3x as causal) and in the BIC (23x as clinically important) databases. It is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 172 and leads to a premature stop codon 62 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735470	SCV000863607	pathogenic	Breast and/or ovarian cancer	2013-12-03	no assertion criteria provided	clinical testing