Submissions for variant NM_007294.4(BRCA1):c.5417del (p.Pro1806fs)

dbSNP: rs80357558

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031250	SCV000300256	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031250	SCV000326308	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571365	SCV000668391	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-08	criteria provided, single submitter	clinical testing	The c.5417delC pathogenic mutation, located in coding exon 21 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 5417, causing a translational frameshift with a predicted alternate stop codon (p.P1806Qfs*28). This alteration occurs at the 3' terminus of theBRCA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 28 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been identified in an individual diagnosed with breast cancer (Foley SB et al. EBioMedicine 2015 Jan;2(1):74-81). This alteration is also known as 5536delC in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001390966	SCV001592875	pathogenic	Hereditary breast ovarian cancer syndrome	2020-05-03	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the BRCA1 gene (p.Pro1806Glnfs*28). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acids of the BRCA1 protein. A different truncation (p.Gln1857Argfs*65) that lies downstream of this variant has been determined to be pathogenic (PMID: 21520333, 11573086, 14576433, 15133503, 25652403). This suggests that deletion of this region of the BRCA1 protein is likely to be causative of disease. This variant is expected to disrupt a portion of the C-terminal region of the BRCA1 protein containing the BRCT domain (residues Val1646-Pro1859) (PMID: 25652403). Although functional studies have not been performed for this particular variant, the BRCT domain is critical for BRCA1 DNA repair activity (PMID: 11573086, 14576433, 15133503, 25652403). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in an individual affected with breast cancer (PMID: 26023681). This variant is also known as 5536delC (p.P1759fs) in the literature. ClinVar contains an entry for this variant (Variation ID: 37669). This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000571365	SCV001735416	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-23	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 22 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003224858	SCV003920906	pathogenic	Familial cancer of breast	2023-05-02	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031250	SCV000053854	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2009-04-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031250	SCV000145506	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing