ClinVar Genomic variation as it relates to human health

Variant summary: The BRIP1 c.3444C>A (p.Asp1148Glu) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant . This variant was found in 15/131898 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000165 (11/66494). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The varaint was reported in the literature in BrC/OvC patients, without strong evidence for causality, as well as in a Lynch syndrome patient who carried a potentially pathogenic MLH1 variant (c.1989+3dupC; Yurgelun_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS, while one classified it as likely benign. Due to the relatively high frequency of the variant in the general population, multiple in silico tools predict benign outcome, as well as the co-occurrence in a patient with a potentially pathogenic variant, this variant has been classified as possibly benign variant until additional evidence becomes available.

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.

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.

Observed in individuals with personal or family history of breast, ovarian and/or other cancers, but also in healthy controls (PMID: 20159562, 21127055, 17033622, 25186627, 26315354, 25980754, 26921362, 33471991, 34326862, 38136308); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 26689913, 25186627, 26315354, 26921362, 17033622, 25980754, 23555315, 33471991, 20159562, 21127055, 38136308, 34326862)

The BRIP1 c.3444C>A; p.Asp1148Glu variant (rs28997573) is reported in the literature in individuals with hereditary cancer syndromes but is also reported in healthy controls (Bhai 2021, Ramus 2015, Seal 2006, Tung 2015, Yurgelun 2015). This variant is also reported in ClinVar (Variation ID: 133758). It is observed in the general population with an overall allele frequency of 0.01% (29/281212 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.072). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bhai P et al. Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. Front Genet. 2021 Jul 13;12:698595. PMID: 34326862. Ramus SJ et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst. 2015 Aug 27;107(11):djv214. PMID: 26315354. Seal S et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006 Nov;38(11):1239-41. PMID: 17033622. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. PMID: 25186627. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. PMID: 25980754.

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1148 of the BRIP1 protein (p.Asp1148Glu). This variant is present in population databases (rs28997573, gnomAD 0.02%). This missense change has been observed in individual(s) with Lynch syndrome, ovarian cancer, breast cancer, and renal clear cell carcinoma (PMID: 25186627, 25980754, 26315354, 26689913). ClinVar contains an entry for this variant (Variation ID: 133758). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.

Variant interpreted as Uncertain significance and reported on 09-15-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.