Submissions for variant NM_007294.4(BRCA1):c.5517_5518insC (p.Asp1840fs)

dbSNP: rs1597796956

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817388	SCV000957943	pathogenic	Hereditary breast ovarian cancer syndrome	2024-09-12	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the BRCA1 gene (p.Asp1840Argfs*40). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the BRCA1 protein and extend the protein by 15 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). 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: 660234). This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 7894493, 10811118, 11739404, 12400015, 21922593; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000817388	SCV002074535	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5517_5518insC (p.Asp1840ArgfsX40) causes a frameshift which results in an extension of the protein. This variant is located in the last exon and is unlikely to result in nonsense mediated decay, but is predicted to replace the last 24 amino acids, creating a new downstream translational stop signal in the last exon and lengthening the C-terminus of the protein. The variant was absent in 251360 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5517_5518insC in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, this frameshift is located in C-terminus of the protein and affects a part of BRCT domain (IPR001357, 1756-1855), which is important for DNA repair activity. Additionally, other downstream deleterious variants were classified as likely pathogenic/pathogenic in our laboratory and ClinVar database. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV004949993	SCV005550040	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-03	criteria provided, single submitter	clinical testing	The c.5517_5518insC pathogenic mutation, located in coding exon 22 of the BRCA1 gene, results from an insertion of one nucleotide at position 5517, causing a translational frameshift with a predicted alternate stop codon (p.D1840Rfs*40). 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 15 amino acids. This frameshift impacts the last 24amino 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). As such, this alteration is interpreted as a disease-causing mutation.