Submissions for variant NM_007294.4(BRCA1):c.3340G>T (p.Glu1114Ter)

dbSNP: rs80357278

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)	RCV000112073	SCV000299925	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112073	SCV000325624	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	RCV000496843	SCV001360669	pathogenic	Hereditary breast ovarian cancer syndrome	2019-12-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3340G>T (p.Glu1114X) 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 250248 control chromosomes (gnomAD). c.3340G>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Kang_2002, Rebbeck_2018, Bhaskaran_2019). 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. Two ClinVar submitters (evaluation after 2014) including one expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000496843	SCV001579543	pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1114*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54849). This variant is also known as 3459G>T, E1114X. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 12204006). This variant is not present in population databases (gnomAD no frequency).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112073	SCV000144728	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-06-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496843	SCV000587302	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research