ClinVar Genomic variation as it relates to human health

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.8902 (African), derived from 1000 genomes (2012-04-30).

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.

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

This variant is not expected to have clinical significance because it does not a lter an amino acid residue and is not located within the splice consensus sequen ce. It has been identified in over 99% of total chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs206076).

High frequency in a 1kG or ESP population: 99.9 %.

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 p.Val2171Val variant has been identified in 8 out of 888 proband chromosomes (frequency 0.009) in individuals with breast and ovarian cancer phenotype, and also identified in 16 of 438 control chromosomes (frequency 0.037), therefore increasing the likelihood of this variant to be benign (Wagner 1999, Fackenthal 2005, Manguoglu 2001, Giannini 2006, Morgan 2010). This variant is also listed in dbSNP database as coming from a "clinical source" (ID#: rs206076) with an average heterozygosity of 0.061+/-0.164 in diverse human population, further suggesting the benign nature of this variant. This variant is not expected to have clinical significance because it does not alter an amino acid residue, and is not located near a splice junction, and in the UMD database, it has been identified in 11 (out of 48) individuals with breast or ovarian cancers, where a second pathogenic BRCA1 or BRCA2 mutation was also detected. In addition, Myriad genetics has reported this variant as a polymorphism increasing the likelihood this variant is benign (personal communication). In summary, based on the above information, this variant is classified as benign