ClinVar Genomic variation as it relates to human health

The p.R855H variant (also known as c.2564G>A), located in coding exon 17 of the BRIP1 gene, results from a G to A substitution at nucleotide position 2564. The arginine at codon 855 is replaced by histidine, an amino acid with highly similar properties. In one study, this alteration was observed in 1/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). This variant was also reported in one individual with early onset breast cancer but was absent from controls (Easton DF et al. J. Med. Genet. 2016 05;53:298-309). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Variant summary: BRIP1 c.2564G>A (p.Arg855His) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal (IPR006555) of 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 6.3e-05 in 268654 control chromosomes. The observed variant frequency is higher than 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 benign. The variant, c.2564G>A, has been reported in the literature in individuals affected with LS, pancreatic, breast, and colon cancer (Yurgelun_2015, Dudley_2018, Easton_2016, Schubert_2019) but also in healthy controls (Ramus_2015). These report(s) do not 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. The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 26315354, 29360161, 30426508, 26921362). ClinVar contains an entry for this variant (Variation ID: 128175). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

The BRIP1 c.2564G>A (p.Arg855His) missense change has a maximum subpopulation frequency of 0.032% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 26921362, 31206626), pancreatic and colon cancer (PMID: 29360161), and prostate cancer (PMID: 32832836). One individual with this variant is also reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 855 of the BRIP1 protein (p.Arg855His). This variant is present in population databases (rs200894063, gnomAD 0.03%). This missense change has been observed in individual(s) with a Lynch syndrome-associated cancer and/or colorectal polyps and breast cancer (PMID: 25980754, 26921362). ClinVar contains an entry for this variant (Variation ID: 128175). 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 with a negative 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.

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.

The frequency of this variant in the general population, 0.00032 (8/24962 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMID: 25980754 (2015)) and breast cancer (PMIDs: 31822495 (2020), 26921362 (2016)), as well as one healthy control individual (PMID: 26315354 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

This missense variant replaces arginine with histidine at codon 855 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and Lynch syndrome-associated cancer and/or polyps (PMID: 25980754, 26921362). This variant has been identified in 20/282682 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Observed in individuals with breast cancer, ovarian cancer or Lynch syndrome-associated cancer and/or polyps, but also in healthy controls (PMID: 26315354, 25980754, 26921362, 31206626, 33471991, 35534704); 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: 26921362, 26315354, 25980754, 33471991, 31206626, 35534704)

The BRIP1 c.2564G>A variant is predicted to result in the amino acid substitution p.Arg855His. This variant has been reported in individuals with a history of breast, pancreatic, and Lynch syndrome-associated cancers (Supplemental Table 2, Yurgelun et al. 2015. PubMed ID: 25980754; Easton et al. 2016. PubMed ID: 26921362; Supporting Table 1, Dudley et al. 2018. PubMed ID: 29360161; Table S3, Weitzel et al. 2019. PubMed ID: 31206626; Table S22, Dorling et al. 2021. PubMed ID: 33471991). However, it has also been reported in control cohorts (Supplementary Table 4, Ramus et al. 2015. PubMed ID: 26315354; Table S3, Weitzel et al. 2019. PubMed ID: 31206626; Table S22, Dorling et al. 2021. PubMed ID: 33471991). This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128175/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.