ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2087C>T (p.Pro696Leu) (rs147755155)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212318 SCV000150044 uncertain significance not provided 2018-06-06 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2087C>T at the cDNA level, p.Pro696Leu (P696L) at the protein level, and results in the change of a Proline to a Leucine (CCA>CTA). This variant has been observed in both breast cancer cases and control groups (Easton 2016, Weber-Lassalle 2018). BRIP1 Pro696Leu was observed at an allele frequency of 0.008% (10/126,608) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the Helicase domain IV (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 Pro696Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000116135 SCV000172898 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000204798 SCV000259556 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 696 of the BRIP1 protein (p.Pro696Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs147755155, ExAC 0.01%). This variant has been observed in individuals affected with breast cancer, as well as unaffected individuals (PMID: 26921362, 29368626). ClinVar contains an entry for this variant (Variation ID: 128167). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Color RCV000116135 SCV000684181 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-07 criteria provided, single submitter clinical testing
Counsyl RCV000662731 SCV000785500 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-10-19 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000212318 SCV000885124 uncertain significance not provided 2018-06-11 criteria provided, single submitter clinical testing The BRIP1 c.2087C>T; p.Pro696Leu variant (rs147755155) is reported in the literature in six individuals with breast cancer, and one unaffected control (Easton 2016). This variant is reported as uncertain by multiple laboratories in ClinVar (Variation ID: 128167), and is found in the general population with an overall allele frequency of 0.005% (13/277092 alleles) in the Genome Aggregation Database. The proline at codon 696 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Pro696Leu variant is uncertain at this time. REFERENCES Easton DF et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J Med Genet. 2016 May;53(5):298-309.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212318 SCV000889206 uncertain significance not provided 2018-05-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781170 SCV000919049 uncertain significance not specified 2019-04-15 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.2087C>T (p.Pro696Leu) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal (IPR006555) domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.3e-05 in 255354 control chromosomes (gnomAD and Easton_2016). This frequency is similar to the maximum expected frequency for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer (6.3e-05 vs 6.3e-05). c.2087C>T has been reported in the literature in individuals affected with breast cancer (Easton_2016, Weber-Lassalle_2018). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 uncertain significance.

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