Submissions for variant NM_032043.3(BRIP1):c.2324A>G (p.Asn775Ser)

gnomAD frequency: 0.00003  dbSNP: rs571108955

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165749	SCV000216492	likely benign	Hereditary cancer-predisposing syndrome	2022-09-29	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	RCV000656813	SCV000278901	uncertain significance	not provided	2023-10-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, ovarian, or other cancers, as well as both cases and unaffected controls in several cancer studies (Lu et al., 2015; Balllinger et al., 2016; Lin et al., 2016; Chan et al., 2018; Terashima et al., 2019; Wang et al., 2019; Momozawa et al., 2019; Okawa et al., 2023); This variant is associated with the following publications: (PMID: 30093976, 26689913, 26824983, 24728327, 25783483, 26580448, 27498913, 32566746, 31666926, 30982232, 11301010, 36243179, 35171259, 31214711, 29929473)
Color Diagnostics, LLC DBA Color Health	RCV000165749	SCV000537560	likely benign	Hereditary cancer-predisposing syndrome	2019-11-25	criteria provided, single submitter	clinical testing
Invitae	RCV000475545	SCV000547288	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 775 of the BRIP1 protein (p.Asn775Ser). This variant is present in population databases (rs571108955, gnomAD 0.2%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, sarcoma, stomach cancer, prostate cancer, and neuroblastoma (PMID: 26580448, 26689913, 26824983, 27498913, 30093976, 30982232, 31214711). ClinVar contains an entry for this variant (Variation ID: 133753). 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 not expected to disrupt BRIP1 protein function. 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	RCV000663063	SCV000786124	uncertain significance	Fanconi anemia complementation group J; Neoplasm of ovary	2018-02-27	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030536	SCV001193532	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120397	SCV001361206	uncertain significance	not specified	2019-10-10	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2324A>G (p.Asn775Ser) results in a conservative amino acid change located in the ATP-dependent helicase, C-terminal domain 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 0.00013 in 251318 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 27.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Breast Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2324A>G has been reported in the literature in individuals affected with breast, ovarian, stomach, and prostate cancers and neuroblastoma without strong evidence of causality (Chan_2018, Lin_2016, Lu_2015, Momozawa_2019, Wang_2019, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS- possibly benign.
Genetic Services Laboratory, University of Chicago	RCV000120397	SCV002068811	uncertain significance	not specified	2018-03-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315735	SCV004019490	likely benign	Familial cancer of breast	2023-03-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
Baylor Genetics	RCV003315735	SCV004214638	uncertain significance	Familial cancer of breast	2023-10-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492523	SCV004240394	uncertain significance	Breast and/or ovarian cancer	2023-05-25	criteria provided, single submitter	clinical testing
ITMI	RCV000120397	SCV000084549	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000165749	SCV000787965	uncertain significance	Hereditary cancer-predisposing syndrome	2018-02-07	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000120397	SCV001364470	benign	not specified	2019-08-13	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656813	SCV001551988	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRIP1 p.Asn775Ser variant was identified in 1 of 266 proband chromosomes (frequency: 0.004) from Taiwanes individuals or families with breast cancer (Lin 2016). The variant was also identified in dbSNP (ID: rs571108955) as “With Uncertain significance allele”, ClinVar (4x, uncertain significance), Clinvitae (3x), and was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 31 of 277046 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24026 chromosomes (freq: 0.00004) and East Asian in 30 of 18840 chromosomes (freq: 0.002), while not observed in the Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Asn775 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of Serine to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153386	SCV003843730	likely pathogenic	Ovarian cancer	2022-01-01	flagged submission	clinical testing