rs145855459

Description

Variant summary: The BRIP1 c.3378A>C (p.Glu1126Asp) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant . This variant was found in 26/121034 control chromosomes (1 homozygote), predominantly observed in the African subpopulation at a frequency of 0.002549 (26/10200). This frequency is about 41 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance and another lab classified this variant as likely benign, all without evidence to independently evaluate. One internal sample also carried a pathogenic variant in RAD51C gene, further supporting the benign classification of the variant of interest. Taken together, this variant is classified as benign.

The BRIP1 p.Glu1126Asp variant was identified in 5 of 29146 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer or Lynch syndrome and was not identified in 10484 control chromosomes from healthy individuals (Easton 2016, Rodriquez-Flores 2014, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs145855459) as "With Uncertain significance allele", ClinVar (classified as benign by Integrated Genetics/Laboratory Corporation of America; as likely benign by Invitae, Ambry Genetics, and GeneDx; and as uncertain significance by two submitters), and the Zhejiang University Database (1x). The variant was not identified in Cosmic or MutDB. The variant was identified in control databases in 70 of 276548 chromosomes (1 homozygous) at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 69 of 24024 chromosomes (freq: 0.003) and Latino in 1 of 34412 chromosomes (freq: 0.00003), while the variant was not observed in the Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Glu1126 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.

in silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene