rs4987050

Description

The BRIP1 p.Asp1153= variant was not identified in the literature nor was it identified in the Cosmic, MutDB, and Zhejiang University databases. The variant was identified in dbSNP (ID: rs4987050) as with uncertain significance allele, in the ClinVar database as benign by GeneDx, Invitae; as likely benign by Ambry Genetics, Counsyl, Color Genomics, Quest Diagnostics, Nichols Institute San Juan Capistrano and ARUP Laboratories; and with uncertain significance by Illumina Clinical Services. The variant was identified in control databases in 201 of 275956 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). In addition, the variant was identified in the1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and in the NHLBI GO Exome Sequencing Project in 6 of 8598 European American and in 1 of 4406 African American alleles. The variant was observed in the following populations: African in 3 of 24010 chromosomes (freq: 0.0001), Other in 18 of 6450 chromosomes (freq: 0.003), Latino in 36 of 34368 chromosomes (freq: 0.001), European Non-Finnish in 116 of 126504 chromosomes (freq: 0.001), Ashkenazi Jewish in 14 of 10146 chromosomes (freq: 0.001), and South Asian in 14 of 30730 chromosomes (freq: 0.0005), while the variant was not observed in the East Asian, European Finnish populations. The p.Asp1153= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.

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 alteration is classified as likely benign based on a combination of the following: 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.

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.