Submissions for variant NM_007294.4(BRCA1):c.1252G>T (p.Glu418Ter)

dbSNP: rs80357083

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)	RCV000111573	SCV000299564	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	RCV000111573	SCV000324996	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566344	SCV000660936	pathogenic	Hereditary cancer-predisposing syndrome	2018-07-26	criteria provided, single submitter	clinical testing	The p.E418* pathogenic mutation (also known as c.1252G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 1252. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation was identified in one Croatian woman diagnosed with ovarian cancer at age 51 and breast cancer at age 54; she also had a family history of both early onset breast and ovarian cancers (Levanat S et al. Gene 2012 May;498:169-76). This mutation has also been identified in a Chinese breast cancer cohort (Sun J et al. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119). 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.
Color Diagnostics, LLC DBA Color Health	RCV000566344	SCV000682942	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-07	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with breast cancer (PMID: 22366370). This variant has not been identified 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	RCV001852985	SCV002172257	pathogenic	Hereditary breast ovarian cancer syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu418*) 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 cancer and/or ovarian cancer (PMID: 22366370, 28724667, 29446198, 30702160). ClinVar contains an entry for this variant (Variation ID: 54176). For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111573	SCV000144040	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1998-03-04	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000111573	SCV002589079	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing