ClinVar Genomic variation as it relates to human health

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.03455 (African), derived from 1000 genomes (2012-04-30).

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.

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: Ben by expert panel

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 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 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.

Converted during submission to Benign.

The p.Ile2944Phe variant has been previously reported in the literature (Johnson 2007, Wagner 1999, Fackenthal 2005, Kim 2005). It has been previously identified in 6 out of 2146 proband chromosomes (frequency 0.003) in individuals with Breast Cancer, and in 3 out of 5110 control chromosomes (frequency 0.001). The Exome Variant Server has listed this variant in 1 out of 8599 genotype counts in a European American population, and 181 out 4225 genotype counts (frequency: 0.043) in an African American population, consistent with the observation that this variant was seen primarily in individuals of African decent in the literature above, and increasing the likelihood this is a common or benign polymorphism. This variant is listed in the BIC database under 115 entries as a variant with unknown clinical importance. It is also listed in the dbSNP database (ID#: rs4987047) with a minor allele frequency of 0.008 (1000 genomes) and up to 15% in some populations. The p.Ile2944 residue is conserved in the mammals and lower species examined, except in Opposum and Zebrafish where a Leucine (Leu) was present at this position, and increasing the likelihood an alteration to this residue may not have functional significance. In the UMD database, this variant has been identified in 1 out of 4 individuals with breast or ovarian cancers, where a second pathogenic BRCA2 mutation was also detected. In addition, this variant was previously identified by our laboratory in one individual who had a second pathogenic variant in the BRCA1 gene, increasing the likelihood the p.Ile2944Phe variant is benign. Computational analyses (AlignGVGD, PolyPhen2, SIFT, BLOSUM) provide inconsistent predictions regarding the impact to the protein; however, this information is not predictive enough to assume pathogenicity. However, functional studies including protein structure prediction, detection of full-length protein, no homologous recombination, no effect on splicing, and sensitivity to DNA damaging reagents, predict this variant to be "non-pathogenic" (Biswas 2012). Finally, Myriad reports this variant as a polymorphism (personal communication). In summary, 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 Benign.