Submissions for variant NM_007294.4(BRCA1):c.4225C>T (p.Gln1409Ter)

dbSNP: rs886040218

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)	RCV000256907	SCV000323744	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	RCV000256907	SCV000325902	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV000536293	SCV000635955	pathogenic	Hereditary breast ovarian cancer syndrome	2021-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1409*) 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 variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 266461). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000570823	SCV000661147	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-09	criteria provided, single submitter	clinical testing	The p.Q1409* pathogenic mutation (also known as c.4225C>T), located in coding exon 11 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4225. This changes the amino acid from a glutamine to a stop codon within coding exon 11. 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). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759536	SCV000888912	pathogenic	not provided	2017-12-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000570823	SCV001345916	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 12 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 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000256907	SCV001428895	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-04-18	criteria provided, single submitter	clinical testing