Submissions for variant NM_032043.3(BRIP1):c.778A>G (p.Thr260Ala)

gnomAD frequency: 0.00002  dbSNP: rs138743097

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123365	SCV000166688	likely benign	Familial cancer of breast; Fanconi anemia complementation group J	2025-01-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000586716	SCV000210869	likely benign	not provided	2020-12-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26315354, 28135145, 26976419, 26921362, 28076423, 28968953, 29641532, 32959997)
Ambry Genetics	RCV000160362	SCV000215637	likely benign	Hereditary cancer-predisposing syndrome	2019-03-30	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267867	SCV000699734	likely benign	not specified	2024-04-25	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.778A>G (p.Thr260Ala) results in a non-conservative amino acid change located in the RAD3-like helicase, DEAD (IPR010614) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 1614008 control chromosomes, predominantly at a frequency of 0.00016 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.56 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.778A>G has been reported in the literature in individuals affected with breast cancer or colorectal cancer without strong evidence of causality (e.g. Tung_2016, Yurgelun_2017, Uyisenga_2020, Nassar_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 136154). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000160362	SCV000911045	likely benign	Hereditary cancer-predisposing syndrome	2016-03-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001125839	SCV001284962	likely benign	Fanconi anemia complementation group J	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586716	SCV002046632	uncertain significance	not provided	2024-09-21	criteria provided, single submitter	clinical testing	The BRIP1 c.778A>G (p.Thr260Ala) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 36672847 (2022), 33471991 (2021), 32959997 (2020), 26976419 (2016), 26921362 (2016), see also LOVD (http://databases.lovd.nl/shared)) and colorectal cancer (PMID: 28135145 (2017)). It has also been observed in reportedly healthy individuals (PMIDs: 26315354 (2015), 26921362 (2016), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000039 (5/128872 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225394	SCV002505044	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160362	SCV002529232	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267867	SCV002551200	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149846	SCV003837716	uncertain significance	Breast and/or ovarian cancer	2021-10-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586716	SCV005892660	uncertain significance	not provided	2024-12-01	criteria provided, single submitter	clinical testing	BRIP1: PM2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005359169	SCV005920016	uncertain significance	Familial ovarian cancer	2022-08-24	criteria provided, single submitter	clinical testing