Submissions for variant NM_007294.4(BRCA1):c.3668_3671dup (p.Cys1225fs)

dbSNP: rs80357797

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112152	SCV000282313	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048279	SCV000076292	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys1225Serfs*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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 12698193, 15728167, 22711857, 26718727). This variant is also known as 3790ins4. ClinVar contains an entry for this variant (Variation ID: 54960). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129597	SCV000184381	pathogenic	Hereditary cancer-predisposing syndrome	2024-12-04	criteria provided, single submitter	clinical testing	The c.3668_3671dupTTCC (p.C1225Sfs*10) alteration, located in exon 10 (coding exon 9) of the BRCA1 gene, consists of a duplication of TTCC at position 3668, causing a translational frameshift with a predicted alternate stop codon after 10 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in multiple individuals with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Scottish/Northern Irish BRCAI/BRCA2, 2003; Claus, 2005; Alsop, 2012; Bernards, 2016; Susswein, 2016; Arvai, 2019). Of note, this alteration is also designated as 3790ins4 and 3790insTTCC in the published literature. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000159921	SCV000210045	pathogenic	not provided	2024-08-13	criteria provided, single submitter	clinical testing	Observed in individuals with personal or family history consistent with hereditary breast and ovarian cancer (PMID: 15728167, 22711857, 26718727); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3671_3672insTTCC, 3790insTTCC, and 3790ins4; This variant is associated with the following publications: (PMID: 12112659, 12698193, 22711857, 15728167, 26681312, 23242139, 26315209, 21295272, 26718727, 33758026)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112152	SCV000325718	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159921	SCV000600340	pathogenic	not provided	2023-01-09	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.0000066 (1/152238 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in several individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 12698193 (2003), 15728167 (2005), 22711857 (2012), 26718727 (2016), 33758026 (2022)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129597	SCV000688446	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This variant inserts 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.3671_3672insTTCC and 3790ins4. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least five individuals affected with breast and ovarian cancer (PMID: 12698193, 15728167, 22711857, 26718727; Color internal data). 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	RCV000048279	SCV003923032	pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3668_3671dupTTCC (p.Cys1225SerfsX10) 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.3668_3671dupTTCC has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Alsop_2012, Scottish-NorthernIrishConsortium_2003, Claus_2005, Evans_2022). These data indicate that the variant is likely to be associated with disease. Seven submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000112152	SCV004215038	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112152	SCV004817768	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-09	criteria provided, single submitter	clinical testing	This variant inserts 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.3671_3672insTTCC and 3790ins4. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least five individuals affected with breast and ovarian cancer (PMID: 15728167, 22711857, 26718727; Color internal data) and in suspected hereditary breast and ovarian cancer families (PMID: 12698193). 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112152	SCV000144833	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048279	SCV000587331	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000159921	SCV000591462	uncertain significance	not provided		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735459	SCV000863596	pathogenic	Breast and/or ovarian cancer		no assertion criteria provided	clinical testing