Submissions for variant NM_032043.3(BRIP1):c.1442G>A (p.Gly481Asp)

gnomAD frequency: 0.00001  dbSNP: rs200062099

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130729	SCV000185619	likely benign	Hereditary cancer-predisposing syndrome	2021-12-29	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	RCV000212311	SCV000210844	uncertain significance	not provided	2022-11-18	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer, prostate cancer, or other cancers (Lu 2015, Ballinger 2016, Hayano 2016, Kim 2016, Wong 2016, Pfaendler 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22578220, 33309985, 31214711, 32566746, 32068069, 24686850, 26790966, 24163242, 25256751, 26689913, 26709662, 27498913, 27701467, 30055942, 29263802, 30723762, 33471991, 29667044)
Color Diagnostics, LLC DBA Color Health	RCV000130729	SCV000537588	likely benign	Hereditary cancer-predisposing syndrome	2020-05-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469846	SCV000547296	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 481 of the BRIP1 protein (p.Gly481Asp). This variant is present in population databases (rs200062099, gnomAD 0.1%). This missense change has been observed in individual(s) with breast cancer (PMID: 26689913, 26790966, 27701467, 29263802, 29667044). ClinVar contains an entry for this variant (Variation ID: 141975). 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 expected to disrupt BRIP1 protein function with a positive 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.
Counsyl	RCV000663131	SCV000786268	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2018-04-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780054	SCV000917075	benign	not specified	2021-03-19	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1442G>A (p.Gly481Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 243572 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 24 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 East Asian origin. c.1442G>A has been reported in the literature in the TGCA cohort (Lu_2015), in studies reporting cohorts of individuals of east asian ancestry undergoing multigene panel testing and in unaffected control cohorts (example, Wong_2016, Kim_2016, Hayano_2016, Ohmoto_2018, Fujita_2020). One of these studies has recently rendered a final classification for this variant a benign among individuals undergoing population-based screening for hereditary colorectal cancer variants in Japan (Fujita_2020). Therefore, none of the ascertained reports 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. Multiple clinical diagnostic laboratories and the LOVD have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (LOVD database-benign, n=1; likely benign, n=1, VUS, n=6). Most submitters reporting a VUS classification cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030540	SCV001193536	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV001124864	SCV001283865	uncertain significance	Fanconi anemia complementation group J	2017-06-12	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4	RCV000130729	SCV002531353	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-09	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315897	SCV004019431	uncertain significance	Familial cancer of breast	2023-03-01	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003315897	SCV004214686	likely benign	Familial cancer of breast	2024-01-23	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000780054	SCV001364523	benign	not specified	2019-08-13	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
PreventionGenetics, part of Exact Sciences	RCV004732695	SCV005356148	uncertain significance	BRIP1-related disorder	2024-04-26	no assertion criteria provided	clinical testing	The BRIP1 c.1442G>A variant is predicted to result in the amino acid substitution p.Gly481Asp. This variant has been identified in individuals with prostate and breast cancer (Lu et al. 2015. PubMed ID: 26689913; Hayano et al. 2016. PubMed ID: 27701467; Kim et al. 2016. PubMed ID: 26790966). This variant is reported in 0.15% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/141975/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.