Submissions for variant NM_007294.4(BRCA1):c.3672del (p.Cys1225fs)

dbSNP: rs398122677

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077129	SCV000299991	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.
Ambry Genetics	RCV000130025	SCV000184851	pathogenic	Hereditary cancer-predisposing syndrome	2019-04-08	criteria provided, single submitter	clinical testing	The c.3672delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 3672, causing a translational frameshift with a predicted alternate stop codon (p.C1225Afs*10). 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	RCV000168007	SCV000218658	pathogenic	Hereditary breast ovarian cancer syndrome	2022-07-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91612). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys1225Alafs*10) 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).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077129	SCV000325720	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000485024	SCV000570870	pathogenic	not provided	2016-06-30	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA1 is denoted c.3672delC at the cDNA level and p.Cys1225AlafsX10 (C1225AfsX10) at the protein level. The normal sequence, with the base that is deleted in braces, is TTCC[C]TGCT. The deletion causes a frameshift which changes a Cysteine to an Alanine at codon 1225, and creates a premature stop codon at position 10 of the new reading frame. Using alternate nomenclature, this variant would be defined as BRCA1 3791delC. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485024	SCV000600342	pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in a hereditary cancer testing cohort (PMID: 31853058 (2020)). It has also been reported in a single family in a large-scale BRCA1/BRCA2 mutation carrier screen (PMID: 29446198 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000130025	SCV000688448	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-07	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168007	SCV002548447	pathogenic	Hereditary breast ovarian cancer syndrome	2022-05-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3672delC (p.Cys1225AlafsX10) 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 251296 control chromosomes. c.3672delC has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). Five clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV003447489	SCV004175654	pathogenic	Peritoneum cancer	2020-10-07	criteria provided, single submitter	clinical testing	The BRCA1 c.3672delC variant is classified as Pathogenic (PVS1, PM2, PP5) This BRCA1 c.3672delC variant is located in exon Missing Exon and is predicted to cause a shift in the reading frame at codon 1225. This variant is absent from population databases (PM2). Absent from gnomAD The variant has been reported in dbSNP (rs398122677) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 91612).
Sharing Clinical Reports Project (SCRP)	RCV000077129	SCV000108926	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-12-27	no assertion criteria provided	clinical testing