ClinVar Genomic variation as it relates to human health

Variant summary: The c.33G>T (p.Gln11His) in BARD1 gene is a missense variant involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at a frequency of 0.3% (115/37748 chrs tested), being most prevalent in Europeans (12/1030chrs tested), which exceeds the maximal expected allele frequency for a non-common pathogenic BARD1 variant (0.0002188). However, ExAC include a warning note that this variant is only covered in 18874 individuals (adjusted allele number = 37748). This means that the site is covered in fewer than 80% of the individuals in ExAC, which may indicate a low-quality site.The variant has been reported in affected individuals without strong evidence for causality. The variant of interest has been reported as Likely Benign/Benign by reputable databases/clinical laboratories. Taken all together, the variant was classified as Benign.

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27978560, 28135145, 25980754, 23056176, 26898890, 26787654, 27328445, 26979391, 27621404, 27498913, 26315354, 28528518, 28873162, 27443514)

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.

BARD1: BS1

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

The BARD1 p.Gln11His variant was identified in 4 of 3420 proband chromosomes (frequency: 0.001) from individuals or families with CRC and Lynch associated cancer (Pearlman 2017, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs143914387) as “with other allele”, and in the ClinVar and Clinvitae databases (as benign by Invitae and likely benign by GeneDx, Ambry Genetics, Illumina Clinical Services, Counsyl, and Quest Diagnostics Nichols Institute San Juan Capistrano). The variant was also identified in the Zhejiang Colon Cancer database 1x but no clinical information was provided. The variant was not identified in the Cosmic and MutDB databases. The variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004) and in the NHLBI GO Exome Sequencing Project in 19 of 7906 European American alleles (freq. 0.002). In addition, the variant was identified in control databases in 344 of 213748 chromosomes (1 homozygous) at a frequency of 0.002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 3 of 18190 chromosomes (freq: 0.0002), Other in 16 of 5410 chromosomes (freq: 0.003), Latino in 72 of 30394 chromosomes (freq: 0.002), European Non-Finnish in 178 of 92742 chromosomes (freq: 0.002), Ashkenazi Jewish in 7 of 8982 chromosomes (freq: 0.0008), European Finnish in 57 of 16012 chromosomes (freq: 0.004), and South Asian in 11 of 26824 chromosomes (freq: 0.0004) while the variant was not observed in the East Asian population. The p.Gln11His residue is not conserved in mammals and 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.