Submissions for variant NM_007294.4(BRCA1):c.2706_2707dup (p.Cys903fs)

gnomAD frequency: 0.00001  dbSNP: rs80357717

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)	RCV000031064	SCV000299816	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	RCV000132203	SCV000187285	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-05	criteria provided, single submitter	clinical testing	The c.2706_2707dupAT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of AT at nucleotide position 2706, causing a translational frameshift with a predicted alternate stop codon (p.C903Yfs*98). 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	RCV000479257	SCV000296275	pathogenic	not provided	2022-12-23	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, 0.000018 (2/113274 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in an individual with breast and/or ovarian cancer (PMID: 31447099 (2019)), as well as in an individual with a paraganglioma (PMID: 29625052 (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	RCV000031064	SCV000325439	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV000459878	SCV000549364	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys903Tyrfs*98) 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 present in population databases (rs80357717, gnomAD 0.002%). 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: 37483). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000479257	SCV000567213	pathogenic	not provided	2017-09-21	criteria provided, single submitter	clinical testing	The BRCA1 c.2706_2707dupAT duplication causes a frameshift, which changes a Cysteine to a Tyrosine at codon903 in exon 10, and creates a premature stop codon at position 98 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein functionthrough either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Counsyl	RCV000031064	SCV000677646	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-06-03	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000031064	SCV000996213	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-11-19	criteria provided, single submitter	clinical testing	This frameshifting variant in exon 10 of 24 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant is reported as a pathogenic variant in a single publication (PMID: 28152038) and multiple clinical diagnostic laboratories in ClinVar have classified this variant as a pathogenic change for hereditary breast and ovarian cancer syndrome (Variation ID: 37483). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (2/250830) and thus is presumed to be rare. Based on the available evidence, the c.2706_2707dup (p.Cys903TyrfsTer98) variant is classified as pathogenic.
Sema4, Sema4	RCV000132203	SCV002538151	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-23	criteria provided, single submitter	curation
Baylor Genetics	RCV000031064	SCV004212671	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132203	SCV004360260	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-17	criteria provided, single submitter	clinical testing	This variant inserts 2 nucleotides 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 been identified in 2/250830 chromosomes 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000459878	SCV004848518	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-15	criteria provided, single submitter	clinical testing	The p.Cys903TyrfsX98 variant in BRCA1 has been reported in at least 2 individuals with hereditary breast and ovarian cancer (HBOC; Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/, Rady Children's Hospital: ClinVar SCV000996213.1). This variant has also been identified in 0.001% (1/68030) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 903 and leads to a premature termination codon 98 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism for HBOC. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP criteria applied: PS4_Supporting, PM2_supporting, PVS1.
Sharing Clinical Reports Project (SCRP)	RCV000031064	SCV000053660	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-03-31	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031064	SCV000144518	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing