rs431825354
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000059.4(BRCA2):āc.7628A>Gā(p.Tyr2543Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,612,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. Y2543Y) has been classified as Likely benign.
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.7628A>G | p.Tyr2543Cys | missense_variant | 16/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7628A>G | p.Tyr2543Cys | missense_variant | 16/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250888Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135660
GnomAD4 exome AF: 0.0000199 AC: 29AN: 1459980Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 726442
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:6Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | This missense variant replaces tyrosine with cysteine at codon 2543 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study reported that this variant impacts BRCA2 function in the rescue of BRCA2-deficient cells in cell viability after mitomycin C treatment and G2/M cell cycle arrest (PMID: 31721781). This variant has been reported in at least five individuals affected with breast cancer (PMID: 30199306, 33471991; Leiden Open Variation Database DB-ID BRCA2_006703, 33773534) and an individual affected with childhood T-cell acute lymphoblastic leukemia (PMID: 31721781). This variant has been identified in 8/250888 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 | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jun 06, 2023 | a point mutation in the BRCA2 gene (c.7628A>G (p.Tyr2543Cys)) which results in the substitution of cysteine for tyrosine at amino acid position 2543. This mutation is considered as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Feb 04, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 06, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | Department of Medical and Surgical Sciences, University of Bologna | Sep 01, 2023 | BS1(Supporting)+BP4(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 08, 2016 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 15, 2022 | The frequency of this variant in the general population, 0.0002 (6/30596 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast cancer (PMID: 30199306 (2018)). Published functional studies have reported inconclusive findings on the effect of this variant on BRCA2 protein function (PMID: 30696104 (2019), 31721781 (2019)). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 31, 2023 | Observed in individuals with a personal history of breast or ovarian cancer (PMID: 30199306, 34271787, 33471991); Published functional studies are inconclusive: proficient binding to DSS1, increased relative mRNA expression and radial chromosome formation similar to wildtype, but reduced relative viability of cells following treatment with mitomycin C (PMID: 30696104, 31721781); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7856A>G; This variant is associated with the following publications: (PMID: 30696104, 31721781, 34271787, 33773534, 30199306, 33471991, 12228710, 32720237, Al-AliA2023[preprint]) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 19, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 20, 2023 | This missense variant replaces tyrosine with cysteine at codon 2543 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study reported that this variant impacts BRCA2 function in the rescue of BRCA2-deficient cells in cell viability after mitomycin C treatment and G2/M cell cycle arrest (PMID: 31721781). This variant has been reported in at least five individuals affected with breast cancer (PMID: 30199306, 33471991; Leiden Open Variation Database DB-ID BRCA2_006703, 33773534) and an individual affected with childhood T-cell acute lymphoblastic leukemia (PMID: 31721781). This variant has been identified in 8/250888 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 | curation | Sema4, Sema4 | Feb 17, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 09, 2022 | The p.Y2543C variant (also known as c.7628A>G), located in coding exon 15 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7628. The tyrosine at codon 2543 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in multiple breast cancer cohorts (Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9; Tariq H et al. Asian Pac J Cancer Prev, 2021 Mar;22:719-724; Chapman-Davis E et al. J Gen Intern Med, 2021 01;36:35-42). This alteration also demonstrated no effect on BRCA2/DSS1 binding in one functional study (Caleca L et al. Cancers (Basel), 2019 Jan;11). 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. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 22, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 06, 2023 | Variant summary: BRCA2 c.7628A>G (p.Tyr2543Cys) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250888 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7628A>G has been reported in the literature as a VUS in individuals affected with breast cancer (example, Abulkhair_2018, Tariq_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One publication reports experimental evidence evaluating an impact on protein function with no impact on BRCA2/DSS1 binding, however the data as presented does not allow convincing conclusions about the variant effect (Caleca_2019). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 16, 2022 | - - |
BRCA2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 31, 2023 | The BRCA2 c.7628A>G variant is predicted to result in the amino acid substitution p.Tyr2543Cys. This variant has been reported in individuals with breast cancer (Abulkhair et al. 2018. PubMed ID: 30199306; Tariq et al. 2021. PubMed ID: 33773534). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32931889-A-G) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/96855/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 04, 2023 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 10, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2543 of the BRCA2 protein (p.Tyr2543Cys). This variant is present in population databases (rs431825354, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 30199306, 33773534). ClinVar contains an entry for this variant (Variation ID: 96855). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 30696104, 31721781). 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