Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000129641 | SCV000184436 | likely benign | Hereditary cancer-predisposing syndrome | 2019-02-07 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Invitae | RCV000551695 | SCV000633031 | uncertain significance | Familial cancer of breast | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 112 of the BARD1 protein (p.Arg112Gln). This variant is present in population databases (rs587781591, gnomAD 0.006%). 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: 141227). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 26350354). 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. |
Color Diagnostics, |
RCV000129641 | SCV000908592 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-05-17 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with glutamine at codon 112 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant protein exhibits homology directed repair activity similar to the wild-type protein in a cell-based assay (PMID: 26350354). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251086 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780950 | SCV000918626 | uncertain significance | not specified | 2018-06-04 | criteria provided, single submitter | clinical testing | Variant summary: BARD1 c.335G>A (p.Arg112Gln) results in a conservative amino acid change located in the RING domain of the encoded protein sequence (Lee_2015). Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 245880 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.335G>A in individuals affected with Hereditary Breast and Ovarian Cancer has been reported. A co-occurrence with another pathogenic variant has been reported (BRCA2 c.8504C>A, p.Ser2835X) in an internal specimen, providing supporting evidence for a benign role. A publication, Lee_2015, functionally assessed the variant and found it to act comparable to wild-type for HDR activity. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign or uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |
Gene |
RCV002512532 | SCV003194982 | uncertain significance | not provided | 2023-01-18 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate homology-directed repair (HDR) activity comparable to wild type (Lee et al., 2015); This variant is associated with the following publications: (PMID: 14647430, 18480049, 26350354) |
Preventiongenetics, |
RCV003407542 | SCV004113561 | uncertain significance | BARD1-related condition | 2023-05-23 | criteria provided, single submitter | clinical testing | The BARD1 c.335G>A variant is predicted to result in the amino acid substitution p.Arg112Gln. This variant is reported to have homology directed repair activity similar to wildtype (Table 1, Lee et al. 2015. PubMed ID: 26350354). This variant is reported in 2 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/2-215657050-C-T). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/141227/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |