Submissions for variant NM_007294.4(BRCA1):c.3442del (p.Glu1148fs)

dbSNP: rs80357808

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031111	SCV000299943	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	RCV000130808	SCV000185704	pathogenic	Hereditary cancer-predisposing syndrome	2019-08-26	criteria provided, single submitter	clinical testing	The c.3442delG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at position 3442, causing a translational frameshift with a predicted alternate stop codon (p.E1148Rfs*7). This mutation has been reported in multiple Japanese, Chinese, and Korean familial breast and ovarian cancer kindreds to date (Sugano et al. Cancer Sci. 2008 Oct;99(10):1967-76; Kurian et al. J Clin Oncol. 2008 Oct 10;26(29):4752-8; Kim et al. Breast Cancer Res Treat. 2012 Aug;134(3):1315-26). 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	RCV000031111	SCV000325658	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	RCV001174630	SCV001337836	pathogenic	Hereditary breast ovarian cancer syndrome	2020-01-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3442delG (p.Glu1148ArgfsX7) 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 251228 control chromosomes. c.3442delG has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (eg. Sugano_2008, Kwon_2019). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories and one expert panel 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	RCV000130808	SCV001345623	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-31	criteria provided, single submitter	clinical testing	This variant deletes 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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple individuals affected with breast and ovarian cancer (PMID: 24249303, 30287823, 30309222). This variant has been identified in 1/251228 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.
Invitae	RCV001174630	SCV001592630	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1148Argfs*7) 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 (rs80357808, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 19016756, 22798144, 28724667, 29020732). This variant is also known as 3561delG. ClinVar contains an entry for this variant (Variation ID: 37530). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000031111	SCV004216939	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-07-21	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031111	SCV000053707	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-02-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031111	SCV000144766	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing