rs75091137

Description

Variant summary: The BRIP1 c.2937A>G (p.Lys979Lys) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predicting no significant impact on splicing and no alteration to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 79/121074 (1 homozygote, 1/1532), predominantly in the African cohort, 75/10358 (1 homozygote, 1/138), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic BRIP1 variant of 1/16000 (0.0000625). Therefore, suggesting the variant is a common polymorphism found in population(s) of African origin. The variant of interest, to our knowledge, has not been reported in affected individuals via publications. However, multiple reputable databases/clinical laboratories cite the variant as "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as 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.

The BRIP1 p.Lys979= variant was not identified in the literature nor was it identified in the ClinVar, Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs75091137) as “With other allele”. The variant was identified in control databases in 171 of 276636 chromosomes (1 homozygous) at a frequency of 0.000618 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 162 (1 homozygous) of 24016 chromosomes (freq: 0.006746), Latino in 8 of 34326 chromosomes (freq: 0.000233), and South Asian in 1 of 30568 chromosomes (freq: 0.000033), while the variant was not observed in the Other, European (Non-Finnish), Ashkenazi Jewish, East Asian, European (Finnish) populations. The p.Lys979= 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 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.