Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001014907 | SCV001175677 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-01-30 | criteria provided, single submitter | clinical testing | The p.E748* variant (also known as c.2242G>T), located in coding exon 11 of the BARD1 gene, results from a G to T substitution at nucleotide position 2242. This changes the amino acid from a glutamic acid to a stop codon within coding exon 11. This alteration occurs at the 3' terminus of BARD1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 29 amino acids of the protein. However, premature stop codons are typically deleterious in nature and structural analysis suggests this alteration results in loss of a large part of a well-ordered C-terminal BRCT domain with destabilization of the structure, which could disrupt protein-protein interactions (Birrane G et al. Biochemistry 2007 Jul; 46(26):7706-12; Feki A et al. Oncogene 2005 May; 24(23):3726-36; Edwards RA et al. Biochemistry 2008 Nov; 47(44):11446-56; Rodriguez M et al. J. Biol. Chem. 2003 Dec; 278(52):52914-8; Ambry internal data). Another truncating alteration downstream, p.V767fs*4 (c.2300_2301delTG), was found to be non-functional in a homology-directed DNA repair through functional studies (Adamovich AI et al. PLoS Genet. 2019 03;15:e1008049). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Invitae | RCV001221656 | SCV001393715 | likely pathogenic | Familial cancer of breast | 2023-06-27 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the C-terminal BRCT domain of BARD1 protein, which is required for chromosome stability and homology-directed repair (PMID: 17848578). A different variant (p.Val767fs) that lies downstream of this variant has been reported to affect BARD1 protein function (PMID: 30925164), this suggests that disruption of this region of the protein is causative of disease. ClinVar contains an entry for this variant (Variation ID: 820952). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu748*) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the BARD1 protein. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001844259 | SCV002103498 | likely pathogenic | Malignant tumor of breast | 2022-02-10 | criteria provided, single submitter | clinical testing | Variant summary: BARD1 c.2242G>T (p.Glu748X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic/likely pathogenic in ClinVar. The variant is not expected to cause nonsense mediated decay, but is expected to impact translation of the last 29 amino acids, including a portion of the BRCT domain (IPR001357). The variant was absent in 251284 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2242G>T in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Myriad Genetics, |
RCV001221656 | SCV004045029 | pathogenic | Familial cancer of breast | 2023-05-25 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. |
Baylor Genetics | RCV001221656 | SCV004217204 | likely pathogenic | Familial cancer of breast | 2023-08-09 | criteria provided, single submitter | clinical testing |