ClinVar Genomic variation as it relates to human health

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

BARD1: BP4, BS1, BS2

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 benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. 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].

This alteration is classified as 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, EXON11, c.2212A>G, p.Ile738Val, Heterozygous, Benign The BARD1 p.Ile738Val variant was identified in 5 of 1030 proband chromosomes (frequency: 0.005) from Polish, Australian and Belgian individuals or families with high risk BRCA1/2 negative breast and/or ovarian cancer and was identified in 5 of 1096 control chromosomes (frequency:0.005) from healthy individuals (Ratajska 2012, Gorringe 2008, De Brakeleer 2010). The variant was identified in a breast tumour, and assessed to be a neutral variant based on a transient apoptosis assay that showed no loss of function (Sauer 2005). In addition, the variant is located with the BRCT functional domain(s) increasing the liklihood that it may have clinical significance; however, protein modelling showed no effect on protein structure or stability (De Brakeleer 2010). The variant was also identified in dbSBP (ID: rs61754118) “With Likely benign allele”, ClinVar (classified benign by GeneDx, Ambry Genetics, Invitae, Vantari Genetics, Color Genomics, and Counsyl; and likely benign by Illumina), Clinivitae (4X) and the Zhejiang Colon Cancer Database (5x), but was not identified in Cosmic and MutDB databases. The variant was identified in control databases in 2066 (21 homozygous) of 277076 chromosomes at a frequency of 0.007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017); being identified in the following populations at a frequency greater than 1%: Ashkenazi Jewish* in 285 of 10150 chromosomes (freq: 0.028), Other in 119 of 6464 chromosomes (freq: 0.018), and Latino in 389 of 34408 chromosomes (freq: 0.011). The p.Ile738Val 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. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.