Submissions for variant NM_007294.4(BRCA1):c.3675C>A (p.Cys1225Ter)

gnomAD frequency: 0.00001  dbSNP: rs879254023

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)	RCV000239174	SCV000323648	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.
GeneDx	RCV000236531	SCV000293200	pathogenic	not provided	2015-09-30	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA1 c.3675C>A at the cDNA level and p.Cys1225Ter (C1225X) at the protein level. The substitution, also reported as 3794C>A (Nahleh 2015), creates a nonsense variant, which changes a Cysteine to a premature stop codon (TGC>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with breast cancer (Nahleh 2015) and is considered pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236531	SCV000296479	pathogenic	not provided	2019-10-08	criteria provided, single submitter	clinical testing	This variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in a cohort of women affected with breast cancer and BRCA1/BRCA2 mutation carriers in the published literature (PMID: 25628955 (2015), 29446198 (2018)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000239174	SCV000325721	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580011	SCV000683121	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-27	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 at least one individual affected with breast cancer (PMID: 25628955). 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.
Ambry Genetics	RCV000580011	SCV001182392	pathogenic	Hereditary cancer-predisposing syndrome	2019-02-06	criteria provided, single submitter	clinical testing	The p.C1225* pathogenic mutation (also known as c.3675C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 3675. This changes the amino acid from a cysteine to a stop codon within coding exon 9. Also referred to as 3794C>A in published literature, this alteration was seen in one Mexican individual with breast cancer (Nahleh Z et al. Am J Cancer Res 2015;5(1):466-71). 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.
Invitae	RCV001383771	SCV001583036	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys1225*) 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 (PMID: 25628955). This variant is also known as c.3794C>A. ClinVar contains an entry for this variant (Variation ID: 245968). For these reasons, this variant has been classified as Pathogenic.