Submissions for variant NM_032043.3(BRIP1):c.1552G>A (p.Val518Ile)

dbSNP: rs786201701

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164112	SCV000214726	likely benign	Hereditary cancer-predisposing syndrome	2019-09-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV001356649	SCV000515452	likely benign	not provided	2020-11-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475560	SCV000547228	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 518 of the BRIP1 protein (p.Val518Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 184796). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000164112	SCV000909778	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-10	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 518 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). The variant amino acid isoleucine is the reference in several mammalian species indicating it is a tolerated change. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000439785	SCV001338392	uncertain significance	not specified	2020-02-25	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1552G>A (p.Val518Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251388 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1552G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356649	SCV001551876	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRIP1 p.Val518Ile variant was not identified in the literature nor was it identified in the following databases: MutDB, Cosmic, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs786201701) as “With Uncertain significance allele”, ClinVar (as likely benign by GeneDx, and as uncertain significance by Ambry Genetics and Invitae), and Clinvitae (3x). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016); it was identified in the Genome Aggregation Database (Feb 27, 2017) in 1 of 111652 European (non-Finnish) chromosomes (freq: 0.0000090) but not in other populations. The p.Val518 residue is not conserved in mammals and the variant amino acid Isoleucine (Ile) is present in rats, mouse, dogs, platypus, and chickens, increasing the likelihood that this variant does not have clinical significance. In addition, 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, 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. This variant is classified as a variant of uncertain significance.