chr13-32325142-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000059.4(BRCA2):āc.383A>Gā(p.Asp128Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,608,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D128A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.383A>G | p.Asp128Gly | missense_variant | 4/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.383A>G | p.Asp128Gly | missense_variant | 4/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251152Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135778
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1456266Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3AN XY: 724848
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Jan 15, 1999 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 16, 2022 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2019 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 12, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 01, 2023 | 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. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 08, 2024 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at