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.

This variant was classified as: Uncertain significance.

This variant is associated with the following publications: (PMID: 26787654, 26976419, 11807980, 28335968, 25980754, 18089818, 23056176, 17972171, 25288723, 17848578, 20077502, 16061562, 22006311, 26738429, 26350354, 9798686, 17550235, 9425226, 26898890, 26517685, 31159747)

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 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.

Variant summary: The BARD1 c.2282G>A (p.Ser761Asn) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 222/129722 control chromosomes (3 homozygotes), predominantly observed in the European (Finnish) subpopulation in ExAC at a frequency of 0.0098366 (65/6608). This frequency is about 45 times the estimated maximal expected allele frequency of a pathogenic BARD1 variant (0.0002188), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. This variant has been reported in affected individuals with comparable MAF as in tested controls. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign, without evidence for independent evaluation. Functional studies showd that variant may lead to defective BARD1 function in growth suppression and apoptosis, however, this variant is shown not to affect the HDR activity. Taken all lines of evidence together, this variant is classified as likely benign until more information becomes available.

BARD1: BP4, BS1

The BARD1 p.Ser761Asn variant was identified in 2 of 1220 proband chromosomes (frequency: 0.002) from individuals or families with breast, ovarian, uterine and endometrial cancers, and was present in 2 of 966 control chromosomes (frequency: 0.002) from healthy individuals (De Brakeleer 2010, Gorringe 2008, Thai 1998). The variant was also identified in dbSNP (ID: rs142155101) as “With Uncertain significance allele”, ClinVar database (1x as benign by Invitae; 3x as likely benign by GeneDx, Ambry Genetics, Illumina; 1x as uncertain significance by CMGUMCL), Clinvitae database (classified as benign by Invitae; classified as likely benign and uncertain significance by ClinVar), MutDB, Zhejiang Colon Cancer Database (LOVD), databases. This variant was identified in the genome Aggregation Database (Genome Aggregation Consortium Feb 27, 2017) in 484 (3 homozygous) of 276958 chromosomes (freq. 0.002), in the following populations: Finnish in 247 of 25792 (2 homozygous) chromosomes (freq. 0.0095), Ashkenazi Jewish in 34 of 10146 chromosomes (freq. 0.0033), European in 189 of 126482 (1 homozygous) chromosomes (freq. 0.0015), other in 7 of 6460 chromosomes (freq. 0.001), Latino in 6 of 34406 chromosomes (freq. 0.00017), African in 1 of 24028 chromosomes (freq. 0.00004), increasing the likelihood this could be a low frequency benign variant. The variant p.Ser761Asn has been identified as cancer-associated missense mutation in breast and uterine cancers (Birrane 2007). This variant was also identified in a screen of 150 sporadic tumors and was not present in normal cells of the patients, indicating that they arose somatically during tumor development (Laufer 2007). The p.Ser761Asn variant was also identified as a somatic variant in endometrial cancer patient at age 8 with associated LOH (Thai 1998).The p.Ser761Asn variant is identified as putative disease associated allele (Sauer 2005).The p.Ser761 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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 but we would lean towards a more benign role for this variant. It is classified as likely benign.