ClinVar Genomic variation as it relates to human health

Variant summary: BARD1 c.568G>A (p.Asp190Asn) results in a conservative amino acid change in the encoded protein sequence. 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 6.3e-05 in 255702 control chromosomes (gnomAD and Ramus_2015) as well as in 5 European American individuals from Flossies database (This cohort consists of both European American and African American women older than 70 years of age but never had cancer). c.568G>A has been reported in the literature in individuals affected with serous ovarian cancer, colorectal cancer and in an individual with a personal history of breast/ovarian cancer without strong evidence of causality (Ramus_2015, Tung_2014, Yurgelun_2017). These reports therefore, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Adamovich_2019). Eight other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=6) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

DNA sequence analysis of the BARD1 gene demonstrated a sequence change, c.568G>A, in exon 4 that results in an amino acid change, p.Asp190Asn. This sequence change has been described in the gnomAD database with a frequency of 0.012% in the non-Finnish European subpopulation (dbSNP rs369561166). The p.Asp190Asn change affects a poorly conserved amino acid residue located in a domain of the BARD1 protein that is not known to be functional. The p.Asp190Asn substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in an individual with colorectal cancer and an individual with serous ovarian cancer (PMID: 28135145, 26315354). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asp190Asn change remains unknown at this time.

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].

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 190 of the BARD1 protein (p.Asp190Asn). This variant is present in population databases (rs369561166, gnomAD 0.01%). This missense change has been observed in individual(s) with ovarian cancer and colorectal cancer (PMID: 26315354, 28135145, 34326862). ClinVar contains an entry for this variant (Variation ID: 142184). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.

Published functional studies suggest no damaging effect: function similar to wild type in a homology directed repair assay (PMID: 30925164); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28135145, 26315354, 27978560, 25186627, 33471991, 34326862, 30925164)

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.

The BARD1 p.Asp190Asn variant was identified in 2 of 3016 proband chromosomes (frequency: 0.0007) from individuals or families with CRC, diagnosed <50 years of age or unselected for family history or MMR tumour status (Pearlman 2016, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs369561166) “With Uncertain significance allele”, ClinVar (classified uncertain significance (2017); submitters: Ambry Genetics, GeneDx, Invitae), and Clinvitae (3x) and was not identified in Cosmic, MutDB, and Zhejiang Colon Cancer Database. The variant was identified in control databases in 15 of 274658 chromosomes at a frequency of 0.00006 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: Latino in 1 of 34134 chromosomes (frequency: 0.00003) and European Non-Finnish in 14 of 125726 chromosomes (frequency: 0001). The p.Asp190 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 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.