Submissions for variant NM_007294.4(BRCA1):c.3764dup (p.Asn1255fs)

dbSNP: rs80357848

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031126	SCV000300011	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048324	SCV000076337	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1255Lysfs*12) 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: 9150171, 26681312). This variant is also known as 3883insA. ClinVar contains an entry for this variant (Variation ID: 37545). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129813	SCV000184627	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-30	criteria provided, single submitter	clinical testing	The c.3764dupA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of A at nucleotide position 3764, causing a translational frameshift with a predicted alternate stop codon (p.N1255Kfs*12). This alteration has been reported in multiple probands with hereditary breast and/or ovarian cancer (Gao Q et al. Am. J. Hum. Genet. 1997 May;60:1233-6; Churpek JE et al. Breast Cancer Res. Treat. 2015 Jan;149:31-9; Palmero E et al. Sci Rep 2018 Jun;8:9188). Of note, this alteration is also designated as 3883insA in published literature. 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031126	SCV000325749	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508668	SCV000605850	pathogenic	not provided	2016-12-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129813	SCV000905031	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant inserts 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. 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.
Baylor Genetics	RCV000031126	SCV004215174	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048324	SCV005203155	pathogenic	Hereditary breast ovarian cancer syndrome	2024-07-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3764dupA (p.Asn1255LysfsX12) 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. The variant was absent in 251272 control chromosomes. c.3764dupA has been reported in the literature in the heterozygous state in at least 1 individual affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Olaya_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36620844). ClinVar contains an entry for this variant (Variation ID: 37545). Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031126	SCV000053725	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-02-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031126	SCV000144869	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1997-11-14	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048324	SCV000587346	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735452	SCV000863589	pathogenic	Breast and/or ovarian cancer	2010-01-20	no assertion criteria provided	clinical testing