Submissions for variant NM_032043.3(BRIP1):c.36G>T (p.Gly12=)

gnomAD frequency: 0.00019  dbSNP: rs45566938

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212296	SCV000167441	benign	not specified	2014-04-08	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.
Ambry Genetics	RCV000124032	SCV000213560	likely benign	Hereditary cancer-predisposing syndrome	2014-07-03	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086934	SCV000252878	benign	Familial cancer of breast; Fanconi anemia complementation group J	2025-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000410111	SCV000404620	uncertain significance	Fanconi anemia complementation group J	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000410111	SCV000490059	likely benign	Fanconi anemia complementation group J	2016-10-26	criteria provided, single submitter	clinical testing
Counsyl	RCV000411186	SCV000490060	likely benign	Ovarian neoplasm	2016-10-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000124032	SCV000684269	likely benign	Hereditary cancer-predisposing syndrome	2015-08-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588076	SCV000699726	benign	not provided	2017-03-16	criteria provided, single submitter	clinical testing	Variant summary: The BRIP1 c.36G>T (p.Gly12Gly) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. The variant lies within a P-loop domain, a helicase domain, a helicase-like DEXD box domain, and a helicase superfamily ATP-binding domain of the protein (InterPro), though none of these domains are listed in the NCBI Conserved Domain database at the variant location. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not signifcantly affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC in 31/121030 control chromosomes, exclusively observed in the European (Non-Finnish) subpopulation at a frequency of 0.000466 (31/66568). This frequency is about 7 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in populations of European (Non-Finnish) origin. Multiple clinical diagnostic laboratories/reputable databases have conflicting classifications for this variant, most of which are benign or likely benign (benign [2x], likely benign [3x], and uncertain significance [2x]). To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212296	SCV001134028	benign	not specified	2020-08-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588076	SCV001151389	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	BRIP1: BP4, BP7
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798416	SCV002043636	likely benign	Breast and/or ovarian cancer	2020-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000124032	SCV002533704	likely benign	Hereditary cancer-predisposing syndrome	2021-02-05	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212296	SCV002551223	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315841	SCV004019407	benign	Familial cancer of breast	2023-03-01	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.