Submissions for variant NM_007294.4(BRCA1):c.4057G>T (p.Glu1353Ter)

dbSNP: rs80357178

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112236	SCV000300064	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000112236	SCV000267708	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001021766	SCV001183421	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-22	criteria provided, single submitter	clinical testing	The p.E1353* pathogenic mutation (also known as c.4057G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4057. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation was identified in one patient with high grade serous ovarian cancer (Weren et al. Hum. Mutat. 2017 02;38(2):226-235). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386122	SCV001586243	pathogenic	Hereditary breast ovarian cancer syndrome	2024-02-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1353*) 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 ovarian cancer (PMID: 27767231). ClinVar contains an entry for this variant (Variation ID: 55090). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800363	SCV002046544	pathogenic	not provided	2020-12-29	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis, and is reported in another study of breast cancer risk (PMID: 15998910 (2005)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001386122	SCV002598867	pathogenic	Hereditary breast ovarian cancer syndrome	2022-09-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4057G>T (p.Glu1353X) 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 251066 control chromosomes. c.4057G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Weren_2017, Park_2020), indicating that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112236	SCV000144950	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing