Submissions for variant NM_000465.4(BARD1):c.2324_2325del (p.Leu775fs)

gnomAD frequency: 0.00001  dbSNP: rs587782046

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130512	SCV000185381	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-21	criteria provided, single submitter	clinical testing	The c.2324_2325delTT variant, located in coding exon 11 of the BARD1 gene, results from a deletion of two nucleotides at nucleotide positions 2324 to 2325. This alteration changes the last three residues of the BARD1 protein and results in the elongation of the protein by 15 amino acids before introducing an alternate stop codon (p.L775Rfs*19). This alteration occurs at the 3' terminus of theBARD1 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 3amino acids of the native protein. The exact functional effect of the altered amino acids is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204402	SCV000260955	uncertain significance	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the BARD1 gene (p.Leu775Argfs*19). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acid(s) of the BARD1 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 BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141836). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the C-terminal BRCT domain of the BARD1 protein. The BRCT domains of BARD1 are required for the chromosome stability maintenance and homology-directed repair activity of the BARD1 protein (PMID: 17848578, 17550235, 26738429). While functional studies have not been performed to directly test the effect of this variant on BARD1 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000679343	SCV000329105	uncertain significance	not provided	2022-07-19	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein extension as the last 3 amino acids are replaced by 18 different amino acids; Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV000130512	SCV000682772	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000204402	SCV000785535	uncertain significance	Familial cancer of breast	2017-09-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679343	SCV000806124	uncertain significance	not provided	2017-12-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780945	SCV000918618	uncertain significance	not specified	2017-10-12	criteria provided, single submitter	clinical testing	Variant summary: The BARD1 c.2324_2325delTT (p.Leu775ArgfsX3+) variant results in a frameshift and a 15 amino acid extension of the protein. One in silico tool predicts a benign outcome for this variant. This variant is absent in 245804 control chromosomes in gnomAD. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as a VUS until additional evidence becomes available.
Baylor Genetics	RCV000204402	SCV004217238	uncertain significance	Familial cancer of breast	2023-07-04	criteria provided, single submitter	clinical testing