Submissions for variant NM_007294.4(BRCA1):c.5569del (p.Gln1857fs)

dbSNP: rs886039675

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254704	SCV000322615	likely pathogenic	not provided	2017-12-26	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA1 is denoted c.5569delC at the cDNA level and p.Gln1857ArgfsX65 (Q1857RfsX65) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCC[delC]AGAT. Using alternate nomenclature, this variant would be defined as BRCA1 5688delC, and has not, to our knowledge, been reported in the literature. The deletion causes a frameshift which changes a Glutamine to an Arginine at codon 1857 in the last exon of the gene, and results in an extension of the protein. The last seven amino acids are replaced with 64 incorrect amino acids, disrupting a region known to interact with multiple proteins (Paul 2014). Based on currently available evidence, we consider this deletion to be a likely pathogenic variant.
Invitae	RCV000465890	SCV000549427	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-05-10	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the BRCA1 gene (p.Gln1857Argfs*65). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the BRCA1 protein and extend the protein by 57 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with BRCA1-related disease (PMID: 21520333; Invitae). ClinVar contains an entry for this variant (Variation ID: 265622). This variant disrupts the C-terminal end of the BRCA1 protein partially including the BRCT domain (residues 1646-1859), which is important for DNA repair activity (PMID: 11573086, 14576433, 15133503, 25652403). While functional studies have not been performed to directly test the effect on BRCA1 protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000465890	SCV000699273	likely pathogenic	Hereditary breast ovarian cancer syndrome	2017-05-15	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.5569delC (p.Gln1857Argfs) variant results in a frame-shift change, predicted to cause a replacement of the last 7 amino acids with 64 incorrect amino acids. Non-sense mediated mRNA decay may not happen since this variant is close the C-terminus. This alteration affects the c-terminus, including part of the BCRT domain, which is important for DNA repair activity. One in silico tool predicts a benign outcome for this variant. This variant is absent in 121000 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Ambry Genetics	RCV002347973	SCV002650896	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	clinical testing	The c.5569delC variant, located in coding exon 22 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 5569, causing a translational frameshift, with a predicted alternate stop codon (p.Q1857Rfs*65). This alteration occurs at the 3' terminus of theBRCA1 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 57 amino acids. This frameshift impacts the last 7 amino acids of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.