ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2564G>A (p.Arg855His) (rs200894063)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589567 SCV000150053 uncertain significance not provided 2018-08-30 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2564G>A at the cDNA level, p.Arg855His (R855H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been observed in at least one individual with breast cancer and another with a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015, Easton 2016). While this variant was not observed among 3,236 ovarian cancer cases, it was identified in 1/3,431 unaffected controls (Ramus 2015). BRIP1 Arg855His was observed at an allele frequency of 0.033% (8/24,024) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Arg855His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000116144 SCV000214409 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-25 criteria provided, single submitter clinical testing 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, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000167924 SCV000218572 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 855 of the BRIP1 protein (p.Arg855His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs200894063, ExAC 0.03%). This variant has been reported in individuals 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). 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: "Possibly 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.
Color RCV000116144 SCV000689345 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589567 SCV000699698 uncertain significance not provided 2016-02-15 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.2564G>A variant affects a conserved nucleotide, resulting in amino acid change from Arg to His. 3/3 in-silico tools predict damaging outcome for this variant (SNPs&GO and MutationTaster not captured due to low reliability index). 4/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 10/128146 control chromosomes at a frequency of 0.000078, which is greater than the maximal expected frequency of a pathogenic BRIP1 allele associated with HBOC (0.0000625). Particularly, the observed frequency in South Asian is ~5-fold greater than the expected allele frequency. [It should be considered that BRIP1 is also associated with FANCJ, which has a maximal expected allele frequency (0.000395), which is not significantly different than the South Asian allele frequency of 0.000303.] Thus based on the frequency comparison, the variant is likely to be benign. In an case-control study, this variant was found in 0/3236 ovarian cancer patients and 1/3431 controls, suggesting that the variant is unlikely to be associated with increased risk of ovarian cancer (Ramus_2015). The variant has also been found in one Lynch Syndrome patient; however, it is uncertain whether the variant explained the phenotype with no cosegregation information provided. Multiple clinical laboratories classified this variant as VUS without evidence to independently evaluate and, from their descriptions in ClinVar, it appears that the ExAC frequency data were not addressed at the time of classification. Taken together, the variant was classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available.
Counsyl RCV000662940 SCV000785897 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2018-01-04 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589567 SCV000887988 uncertain significance not provided 2018-01-30 criteria provided, single submitter clinical testing
Pathway Genomics RCV000144588 SCV000189912 uncertain significance Fanconi anemia, complementation group J 2014-07-24 no assertion criteria provided clinical testing

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