ClinVar Genomic variation as it relates to human health

Variant summary: The BRIP1 c.430G>A (p.Ala144Thr) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 164/121364 control chromosomes (2 homozygotes) at a frequency of 0.0013513, which is approximately 22 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is 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.

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

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 BRIP1 p.Ala144Thr variant was identified in 7 of 3854 proband chromosomes (frequency: 0.002) from Australian, Korean, Chinese and America individuals or families with suspected Lynch Syndrome, or BRCA1/2 negative familial breast cancer, but was not identified in 186 control chromosomes (Yurgelun 2015, Lewis 2005, Kim 2016 , Cao 2009). In one study, the variant cooccurred with BRIP1 c.3401delC, and both variants were not found to segregate with breast cancer, being inherited from the father of the index case who had no personal or family history of breast cancer, and not from the affected mother with a strong family history (Lewis 2005 ). The variant was identified in ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Counsyl; likely benign by Illumina; and classification not provided by ITMI), Clinvitae ( classified as benign 5X, and likely benign 1X), Cosmic (1X in a bladder carcinoma, confirmed as somatic), and the Zhejiang Colon Cancer Database (3X); and was not identified in MutDB. The variant was also identified in control databases in 390 (2 homozygous) of 277018 chromosomes at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), identified in the following population at a frequency greater than 1%: East Asian in 361 of 18862 chromosomes (freq: 0.019). The p.Ala144Thr residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.