ClinVar Genomic variation as it relates to human health

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Variant summary:The c.1933T>C variant involves the alteration of a non-conserved nucleotide and causes change from medium size and polar (C) residue to large size and basic. 4/5 in silico tools predict a benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 1% (779/121331 chromosomes), predominantly observed in the African subpopulation at a frequency of 6.9% (720/10388 chromosomes) including 31 African homozygous occurrences. These frequencies exceed the maximal expected allele frequency for a pathogenic BARD1 variant of 0.0218%, suggesting this is a benign polymorphism found primarily in populations of African origin. One reputable clinical lab has classified this variant as benign (Ambry Genetics). It has previously been reported in patients with breast and ovarian cancer (Sauer 2005) without strong evidence for causality. Functional analyses showed this variant decreased the tumor suppression activity and apoptosis (Sauer 2005) and decreased the binding activity with poly(ADP-ribose) and BRCA1 (Li 2013). However, the in vivo implications of these functional findings have not been confirmed yet. Considering all, especially based on the high allele frequency in population cohorts, this variant is classified as Benign.

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.

The BARD1 p.Cys645Arg variant was identified in 1 of 504 proband chromosomes (frequency: 0.00198) from individuals or families with hereditary breast and ovarian cancer, and was also identified in 3 of 472 control chromosomes (frequency: 0.006) (De Brakeleer_2010_20077502, Sauer_2005_16061562). The variant was also identified in the following databases: dbSNP (ID: rs2228456) as “With Likely benign allele”, ClinVar (as likely benign by Illumina and benign by Ambry Genetics, Color Genomics, Counsyl, Invitae, and Quest Diagnostics), Clinvitae (3x), and Zhejiang Colon Cancer Database (3x). The variant was not identified in Cosmic, or MutDB databases. The variant was identified in control databases in 1841 of 277108 chromosomes (56 homozygous) at a frequency of 0.006644 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 1657 (55 homozygous) of 24032 chromosomes (freq: 0.06895), “Other” in 23 (1 homozygous) of 6464 chromosomes (freq: 0.003558), Latino in 99 of 34416 chromosomes (freq: 0.002877), European (Non-Finnish) in 29 of 126612 chromosomes (freq: 0.000229), Ashkenazi Jewish in 14 of 10148 chromosomes (freq: 0.00138), European (Finnish) in 17 of 25784 chromosomes (freq: 0.000659), and South Asian in 2 of 30782 chromosomes (freq: 0.000065), while the variant was not observed in the East Asian populations. Several functional studies identified the variant to be associated with breast and ovarian cancer, and may adversely affect the structure and function of the BRCT1 domain (Alshatwi_2012_23056176, Birrane_2007_17550235, Li_2013_23680151, Sauer_2005_16061562). The p.Cys645Arg 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 this variant meets our laboratory's criteria to be classified as benign.