Submissions for variant NM_032043.3(BRIP1):c.2748C>T (p.Tyr916=)

gnomAD frequency: 0.00003  dbSNP: rs555200296

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166413	SCV000217208	likely benign	Hereditary cancer-predisposing syndrome	2014-10-15	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000431405	SCV000512423	likely benign	not specified	2017-08-15	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000459998	SCV000558569	likely benign	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000431405	SCV000593763	likely benign	not specified	2016-11-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166413	SCV000684230	likely benign	Hereditary cancer-predisposing syndrome	2016-09-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000431405	SCV002014909	benign	not specified	2021-10-14	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000431405	SCV004026878	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357082	SCV001552423	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.Tyr916= variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs555200296) “With Likely benign allele”, ClinVar (classified likely benign by Ambry Genetics, GeneDx, Invitae, Genetic Services Laboratory (University of Chicago) and Color Genomics Inc), Clinvitae (3x), and in control databases in 17 of 277110 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 17 of 18860 chromosomes (freq: 0.0009); but not in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Tyr916= 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.