ClinVar Genomic variation as it relates to human health

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Also known as BRCA2 611A>G; This variant is associated with the following publications: (PMID: 30287823, 24814045, 10690392, 30883759)

This missense variant replaces aspartic acid with glycine at codon 128 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). A minigene splicing assay has reported a partial splicing defect for this variant (PMID: 30883759). To our knowledge, protein functional studies have not been performed for this variant. This variant has been reported in one individual each affected with breast cancer and colorectal cancer and in two individuals affected with prostate cancer (PMID: 10690392, 24814045, 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA2_006255). This variant also has been reported in at least three individuals unaffected with cancer in breast and pancreatic cancer case-control studies (PMID: 30287823, 32980694, 33471991; Leiden Open Variation Database DB-ID BRCA2_006255). This variant has been identified in 1/251152 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 sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 128 of the BRCA2 protein (p.Asp128Gly). This variant is present in population databases (rs80358627, gnomAD 0.0009%). This missense change has been observed in individual(s) with colorectal cancer, breast cancer and prostate cancer (PMID: 10690392, 24814045, 31214711, 35264596). ClinVar contains an entry for this variant (Variation ID: 51538). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.

Kriterien überprüfen nach ENIGMA Entscheidungsbaum; According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose these criteria: PP3 (supporting pathogenic): SpliceAI: BRCA2: 0.39 , BP7 (strong benign): BP7_STR(RNA); Fraile Bethencourt 2019 Minigene Exons 2–9: Full-Length Transcript 78%; Appendices Guidelines Tbl.9: Cutoff Referenztranskript 30%

Variant summary: BRCA2 c.383A>G (p.Asp128Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1e-05 in 298614 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.383A>G has been reported in the literature in settings of multi-gene panel testing in individuals affected with breast cancer or personal and/or family history of cancer, often reported as a VUS (e.g. Li_2020, Sandoval_2021, Herzog_2021, Guindalini_2022, deOliveira_2022, Gifoni_2022), in colorectal cancer (Garre_2014), or male breast cancer (e.g. Diez_2002), in all cases without evidence of causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A functional study (e.g. Fraile-Bethencourt_2019) using a mini-gene assay found the variant to not significantly impact splicing, predominantly producing the wild type BRCA2 protein. The following publications have been ascertained in the context of this evaluation (PMID: 10690392, 30883759, 24814045, 35957908, 35264596, 34413315, 31853058, 30287823, 33606809, 35534704). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces aspartic acid with glycine at codon 128 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). A minigene splicing assay has reported a partial splicing defect for this variant (PMID: 30883759). To our knowledge, protein functional studies have not been performed for this variant. This variant has been reported in one individual each affected with breast cancer and colorectal cancer and in two individuals affected with prostate cancer (PMID: 10690392, 24814045, 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA2_006255). This variant also has been reported in at least three individuals unaffected with cancer in breast and pancreatic cancer case-control studies (PMID: 30287823, 32980694, 33471991; Leiden Open Variation Database DB-ID BRCA2_006255). This variant has been identified in 1/251152 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.D128G variant (also known as c.383A>G), located in coding exon 3 of the BRCA2 gene, results from an A to G substitution at nucleotide position 383. The aspartic acid at codon 128 is replaced by glycine, an amino acid with similar properties. This variant has been observed in a colorectal cancer kindred (Garre P et al. Clin. Genet., 2015 Jun;87:582-7). This alteration was also detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is poorly 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.