Submissions for variant NM_032043.3(BRIP1):c.1433A>G (p.His478Arg)

gnomAD frequency: 0.00002  dbSNP: rs45501097

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120388	SCV000150034	benign	not specified	2018-02-28	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084447	SCV000166671	benign	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000116125	SCV000183881	benign	Hereditary cancer-predisposing syndrome	2019-05-07	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000409336	SCV000489881	benign	Fanconi anemia complementation group J	2016-07-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000410488	SCV000489882	benign	Ovarian neoplasm	2016-07-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000514890	SCV000600893	benign	not provided	2022-03-29	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514890	SCV000610616	likely benign	not provided	2017-05-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116125	SCV000689260	benign	Hereditary cancer-predisposing syndrome	2017-11-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000409336	SCV001283866	benign	Fanconi anemia complementation group J	2018-01-12	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225333	SCV002505037	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120388	SCV002760982	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315647	SCV004016921	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315647	SCV004019482	likely benign	Familial cancer of breast	2023-03-02	criteria provided, single submitter	clinical testing	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.
ITMI	RCV000120388	SCV000084540	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000514890	SCV001548876	likely benign	not provided		no assertion criteria provided	clinical testing	The BRIP1 p.His478Arg variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs45501097) as With Uncertain significance allele, ClinVar (classified as benign by Invitae, Counsyl; classified as likely benign by GeneDx; classified as uncertain significance by Ambry Genetics), Zhejiang Colon Cancer Database, databases. The variant was not identified in the Cosmic or MutDB databases. The variant was identified in control databases in 493 (8 homozygous) of 270132 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: South Asian in 480 of 29928 chromosomes (freq: 0.016). The p.His478 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, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the DNA helicase (DNA repair), Rad3 type functional domain the clinical significance of which is not known. 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.