Submissions for variant NM_007294.4(BRCA1):c.5368del (p.Ser1790fs)

dbSNP: rs879254116

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000660936	SCV000783174	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-15	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
GeneDx	RCV000235927	SCV000293554	pathogenic	not provided	2015-11-19	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA1 is denoted c.5368delT at the cDNA level and p.Ser1790LeufsX3 (S1790LfsX3) at the protein level. The normal sequence, with the base that is deleted in braces, is TGCT[T]CTGT. Using alternate nomenclature this variant would be defined as BRCA1 5487delT. The deletion causes a frameshift, which changes a Serine to a Leucine at codon 1790, and creates a premature stop codon at position 3 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 function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235927	SCV001133627	pathogenic	not provided	2023-05-02	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. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 28176296 (2017)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804970	SCV002051090	pathogenic	Hereditary breast ovarian cancer syndrome	2021-12-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5368delT (p.Ser1790LeufsX3) 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 251446 control chromosomes (gnomAD). c.5368delT has been reported in the literature in an individual affected with ovarian cancer (Shi_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014, including one expert panel (ENIGMA), and all submitters have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001804971	SCV002052563	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-10	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 21 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, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with ovarian cancer (PMID: 28176296; Ahmad et al. (2020) J Mol Genet Med 14:467). 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.
Fulgent Genetics, Fulgent Genetics	RCV002479945	SCV002786309	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-04-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001804970	SCV003461787	pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-14	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 246134). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 30702160). This sequence change creates a premature translational stop signal (p.Ser1790Leufs*3) 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).
Revvity Omics, Revvity	RCV000235927	SCV003811844	pathogenic	not provided	2022-09-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000660936	SCV004216896	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-10-18	criteria provided, single submitter	clinical testing