Submissions for variant NM_007294.4(BRCA1):c.4120_4121del (p.Glu1373_Ser1374insTer)

dbSNP: rs80357787

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031151	SCV000300076	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.
Ambry Genetics	RCV000131891	SCV000186946	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-06	criteria provided, single submitter	clinical testing	The c.4120_4121delAG pathogenic mutation, located in coding exon 10 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 4120 to 4121, causing a translational frameshift with a predicted alternate stop codon (p.S1374*). This pathogenic mutation has been reported in numerous individuals diagnosed with breast and/or ovarian cancer (Montagna M et al. Cancer Res. 1996 Dec 1;56(23):5466-9; Walsh T et al. Proc Natl Acad Sci USA. 2011 Nov 1;108(44):18032-7; Mannan AU et al J. of Hum. Genetics 2016; 61:515–522; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Bhaskaran SP et al. Int. J. Cancer, 2019 08;145:962-973). Of note, this alteration is also designated as 4239delAG 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	RCV000031151	SCV000325856	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131891	SCV000688467	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-08	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 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 and ovarian cancer (PMID: 8968102, 11595708, 22006311, 28111427, 29446198, 30287823, 30702160; Color internal data) and this variant is reported to cosegregate with cancer in one hereditary breast and ovarian cancer family (PMID: 8968102). 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.
GeneDx	RCV000657802	SCV000779557	pathogenic	not provided	2020-12-10	criteria provided, single submitter	clinical testing	Nonsense 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 individuals with a personal or family history consistent with pathogenic variants in this gene (Montagna 1996, Walsh 2011, Mannan 2016); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4239delAG; This variant is associated with the following publications: (PMID: 28111427, 31924417, 8968102, 26911350, 22762150, 22006311, 26556299, 28176296, 30702160)
3DMed Clinical Laboratory Inc	RCV000677798	SCV000803956	pathogenic	Breast neoplasm	2017-06-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496761	SCV000918799	pathogenic	Hereditary breast ovarian cancer syndrome	2021-01-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4120_4121delAG (p.Ser1374X) 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 was absent in 249128 control chromosomes. c.4120_4121delAG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). 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 and one expert panel (ENIGMA) 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657802	SCV001133577	pathogenic	not provided	2022-09-15	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. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals/families with breast and/or ovarian cancer (PMID: 8968102 (1996), 22006311 (2011), 28111427 (2017), 30287823 (2018)). Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496761	SCV001394184	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1374*) 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/or ovarian cancer (PMID: 8968102, 22006311). This variant is also known as 4239delAG. ClinVar contains an entry for this variant (Variation ID: 37570). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000031151	SCV005058328	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-14	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031151	SCV000053751	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2009-04-30	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031151	SCV000144988	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496761	SCV000587376	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000657802	SCV000591493	pathogenic	not provided		no assertion criteria provided	clinical testing