Submissions for variant NM_007294.4(BRCA1):c.1252dup (p.Glu418fs)

dbSNP: rs886039936

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000256915	SCV000323292	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000256915	SCV000324995	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496510	SCV000954116	pathogenic	Hereditary breast ovarian cancer syndrome	2024-05-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu418Glyfs*4) 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 a personal and/or family history of breast and/or ovarian cancer (PMID: 28324225). This variant is also known as c.1252_1253insG. ClinVar contains an entry for this variant (Variation ID: 266148). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002411138	SCV002675614	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-01	criteria provided, single submitter	clinical testing	The c.1252dupG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of G at nucleotide position 1252, causing a translational frameshift with a predicted alternate stop codon (p.E418Gfs*4). 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). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496510	SCV006086725	pathogenic	Hereditary breast ovarian cancer syndrome	2025-05-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1252dupG (p.Glu418GlyfsX4) 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 was absent in 250828 control chromosomes. c.1252dupG has been observed in individual(s) with a personal and/or family history of Hereditary Breast And Ovarian Cancer Syndrome (Meisel_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28324225). ClinVar contains an entry for this variant (Variation ID: 266148). Based on the evidence outlined above, the variant was classified as pathogenic.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496510	SCV000587115	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research