ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 30309722, 27742771, 28873162, 24123366, 26315354, 26976419, 25980754)

Variant summary: The variant, BARD1 c.620A>G (p.Lys207Arg) 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 0.00075 in 263154 control chromosomes predominantly within the African subpopulation, at a frequency of 0.0072, in the gnomAD database, including 1 homozygote. The observed variant frequency within African control individuals in the gnomAD database is approximately 30 fold of the estimated maximal expected allele frequency for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. In addition, the variant was also reported in 47/2559 African American women (i.e. with a frequency of 0.018), who were older than 70 years of age, and never had cancer (in the FLOSSIES database); further supporting the benign nature of the variant. The variant, c.620A>G has been reported in the literature in an individual affected with ovarian cancer (Ramus 2015) and in three African American individuals affected with breast cancer (Tung 2015), however without evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign (1x)/likely benign (7x). Based on the evidence outlined above, the variant was classified as benign.

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 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.Lys207Arg variant was identified in 3 of 10244 proband chromosomes (frequency: 0.0003) from individuals or families with stages I to III breast and or ovarian cancer, and Lynch Syndrome (Yurgelun_2015_25980754, Tung_2016_26976419, Ramus_2015_26315354). The variant was also identified in dbSNP (ID: rs34969857) as “With other allele”, and in ClinVar and Clinvitae (7x as benign by Invitae, likely benign by GeneDx, Ambry Genetics, Counsyl, Quest Diagnostics, Color Genomics, Laboratory Corporation of America). The variant was not identified in Cosmic, MutDB or the Zhejiang University Database. The variant was identified in control databases in 187 of 257912 chromosomes (1 homozygous) at a frequency of 0.0007 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 166 of 23650 chromosomes (freq: 0.007), Other in 1 of 5942 chromosomes (freq: 0.00017), Latino in 15 of 29648 chromosomes (freq: 0.0005), European Non-Finnish in 5 of 120972 chromosomes (freq: 0.00004); it was not observed in the Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Lys207Arg 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.