Submissions for variant NM_007294.4(BRCA1):c.4123G>T (p.Glu1375Ter)

dbSNP: rs80357397

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)	RCV000112266	SCV000300078	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	RCV000112266	SCV000325858	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV001383616	SCV001582833	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1375*) 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: 29446198). ClinVar contains an entry for this variant (Variation ID: 55108). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003298096	SCV003995311	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-09	criteria provided, single submitter	clinical testing	The p.E1375* pathogenic mutation (also known as c.4123G>T), located in coding exon 10 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4123. This changes the amino acid from a glutamic acid to a stop codon within coding exon 10. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families and was also reported in a woman with invasive bilateral breast cancer diagnosed under the age of 30 (Rebbeck TR et al. Hum Mutat, 2018 May;39:593-620; Evans DG et al. J Med Genet, 2022 Feb;59:115-121). In addition to the clinical information 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112266	SCV000144990	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112266	SCV004244005	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing