rs397507423
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM5BP4_ModerateBP6
The NM_000059.4(BRCA2):c.9253A>C(p.Thr3085Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3085K) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.9253A>C | p.Thr3085Pro | missense_variant | 24/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.9253A>C | p.Thr3085Pro | missense_variant | 24/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000320 AC: 8AN: 250264Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135272
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460476Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6AN XY: 726552
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74356
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 18, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28591715) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 18, 2023 | In the published literature, this variant has been reported in an individual with breast cancer (PMID: 34196900 (2021)) and in an individual with colorectal cancer (PMID: 28591715 (2017)). The frequency of this variant in the general population, 0.0002 (7/34306 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 09, 2016 | Variant summary: The BRCA2 c.9253A>C (p.Thr3085Pro) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome. This variant was found in 1/119814 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been found to co-occur in cis with a pathogenic mutation BRCA2 c.9235delG (p.Val3079PhefsX4) in an LCA sample, suggesting the benign role of the variant. One clinical diagnostic laboratories/reputable databases classified this variant as a VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2024 | The p.T3085P variant (also known as c.9253A>C), located in coding exon 23 of the BRCA2 gene, results from an A to C substitution at nucleotide position 9253. The threonine at codon 3085 is replaced by proline, an amino acid with highly similar properties. This variant was reported in an unselected cohort of Guatemalan breast cancer patients (Ren M et al. Breast Cancer Res Treat, 2021 Sep;189:533-539). This amino acid position is poorly 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 31, 2020 | This missense variant replaces threonine with proline at codon 3085 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 8/250264 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. - |
Hereditary breast ovarian cancer syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jun 02, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 20, 2023 | 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 sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 3085 of the BRCA2 protein (p.Thr3085Pro). This variant is present in population databases (rs397507423, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 38224). 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. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Thr3085Pro variant was not identified in the literature. This residue is not conserved in mammals and the variant residue proline (Pro) is found in opossum, increasing the likelihood this variant does not have clinical significance. Furthermore, computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition, this variant was identified in the presence of a co-occuring pathogenic variant in this individual, increasing the likelihood this variant is benign. In summary, base on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 08, 2009 | - - |
BRCA2-related condition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 17, 2022 | The BRCA2 c.9253A>C variant is predicted to result in the amino acid substitution p.Thr3085Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32954279-A-C). In ClinVar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/38224/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 21, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at