Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000228060 | SCV000284959 | uncertain significance | Familial cancer of breast | 2023-12-31 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 128 of the BARD1 protein (p.Pro128Ser). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 237836). 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 serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. |
Ambry Genetics | RCV000563282 | SCV000668172 | likely benign | Hereditary cancer-predisposing syndrome | 2018-12-29 | 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. |
Color Diagnostics, |
RCV000563282 | SCV000903429 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-07-26 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with serine at codon 128 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/278994 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. |
Illumina Laboratory Services, |
RCV000228060 | SCV001296634 | uncertain significance | Familial cancer of breast | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
Gene |
RCV001354376 | SCV004012379 | uncertain significance | not provided | 2023-07-05 | 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; Has not been previously published as pathogenic or benign to our knowledge |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003387815 | SCV004099617 | uncertain significance | not specified | 2023-09-01 | criteria provided, single submitter | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV001354376 | SCV001548981 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The BARD1 p.Pro128Ser variant was not identified in the literature nor was it identified in the Cosmic, MutDB, and the Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs878854011) as “with uncertain significance allele”, in the ClinVar database as likely benign by Invitae and as uncertain significance by Ambry Genetics. The variant was not identified in the 1000 Genomes Project or in the NHLBI GO Exome Sequencing Project databases. The variant was identified in control databases in 3 of 273386 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). It was observed in the European Non-Finnish population in 3 of 124658 chromosomes (freq: 0.00002); the was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Pro128Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The identification of this variant in an individual from our laboratory with a co-occurring pathogenic variant (ATM, EXON49, c.7271T>G), in the context of a breast cancer referral, albeit in a different gene, increased the likelihood the BARD1 p.Pro128Ser may not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |