rs587780248

Description

Variant reported in individuals with breast and ovarian cancer (Lu 2015, Ramus 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26689913, 26315354)

This missense variant replaces glutamic acid with glutamine at codon 1111 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in one individual each affected with breast cancer (PMID: 26689913) and ovarian cancer (PMID: 26315354). This variant has been identified in 6/282292 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.

The p.E1111Q variant (also known as c.3331G>C), located in coding exon 19 of the BRIP1 gene, results from a G to C substitution at nucleotide position 3331. The glutamic acid at codon 1111 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a breast cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec;6:10086). In another 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 amino acid position is not 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.

The BRIP1 p.Glu1111Gln variant was identified in 1 of 6472 proband chromosomes (frequency: 0.0002) from individuals or families with ovarian cancer and was not identified in 6862 control chromosomes from healthy individuals (Ramus 2015 ). The variant was also identified in dbSNP (ID: rs587780248) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics, Counsyl, Color Genomics) databases. The variant was not identified in Cosmic, or Zhejiang University databases. The variant was identified in control databases in 5 of 276776 chromosomes at a frequency of 0.000018 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 5 of 126324 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Glu1111 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

This sequence change replaces glutamic acid with glutamine at codon 1111 of the BRIP1 protein (p.Glu1111Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs587780248, ExAC 0.003%). This missense change has been observed in individual(s) with ovarian and breast cancer (PMID: 26315354, 26689913). ClinVar contains an entry for this variant (Variation ID: 128186). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.

Variant summary: BRIP1 c.3331G>C (p.Glu1111Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 276776 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lu_2015, Ramus_2015). 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. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.