ClinVar Genomic variation as it relates to human health

The p.R2888H variant (also known as c.8663G>A), located in coding exon 20 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8663. The arginine at codon 2888 is replaced by histidine, an amino acid with highly similar properties. This alteration was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0001 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 Oct;9:4083). This alteration has also been reported with a carrier frequency of 0.00000 in 7636 unselected prostate cancer patients and 0.00008 in 12366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376). This amino acid position is not 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.

According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose this criterion: BP4 (supporting benign): BayesDel no-AF -0.1726, SpliceAI 0.01

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with breast cancer, and co-occurred with an MSH2 pathogenic variant in an individual with colorectal cancer (Kraus 2017, Hampel 2018); This variant is associated with the following publications: (PMID: 27616075, 29596542, 31131967)

In the published literature, this variant has been reported in an individual with breast cancer (PMID: 29596542 (2018)), as well as in healthy control individuals over the age of 60-70 in Japan (PMIDs: 36243179 (2022), 31214711 (2020), 30287823 (2018)). This variant has also been observed in an individual with colon cancer who carried a deleterious variant in the MSH2 gene (PMID: 29596542 (2018)). The frequency of this variant in the general population, 0.000011 (3/282684 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2888 of the BRCA2 protein (p.Arg2888His). This variant is present in population databases (rs80359124, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 52651). 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 BRCA2 protein function with a negative predictive value of 95%. 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 missense variant replaces arginine with histidine at codon 2888 of the BRCA2 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 reported in an individual affected with breast cancer (PMID: 27616075) and in a breast cancer case-control meta-analysis in 3/60463 cases and 1/53460 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_006568). This variant also has been reported in three Japanese case-control studies on breast, pancreatic and prostate cancer, in which this variant was detected in one unaffected individual per study and was absent in cancer cases (PMID: 30287823, 31214711, 32980694). This variant has been identified in 3/282684 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.

This missense variant replaces arginine with histidine at codon 2888 of the BRCA2 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 reported in an individual affected with breast cancer (PMID: 27616075) and in a breast cancer case-control meta-analysis in 3/60463 cases and 1/53460 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_006568). This variant also has been reported in three Japanese case-control studies on breast, pancreatic and prostate cancer, in which this variant was detected in one unaffected individual per study and was absent in cancer cases (PMID: 30287823, 31214711, 32980694). This variant has been identified in 3/282684 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.