ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2324A>G (p.Asn775Ser) (rs571108955)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165749 SCV000216492 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000656813 SCV000278901 uncertain significance not provided 2018-12-30 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2324A>G at the cDNA level, p.Asn775Ser (N775S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant was observed in at least one individual with stomach adenocarcinoma and at least one individual with breast cancer (Lu 2015, Lin 2016). BRIP1 Asn775Ser was also identified in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Bodian 2014); however, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant. BRIP1 Asn775Ser was observed at an allele frequency of 0.16% (30/18,840) in individuals of East Asian ancestry in large population cohorts (Lek 2016). BRIP1 Asn775Ser is located within the helicase domain V (Cantor 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Asn775Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color 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 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 775 of the BRIP1 protein (p.Asn775Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs571108955, ExAC 0.2%). This variant has been reported in the literature in an individual with breast cancer and/or a family history of breast and ovarian cancer (PMID: 26824983) and an individual affected with stomach adenocarcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 133753). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America 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.
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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.