rs276174923
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4BP6
The NM_000059.4(BRCA2):āc.9344A>Gā(p.Lys3115Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 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. K3115N) 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.9344A>G | p.Lys3115Arg | missense_variant | 25/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.9344A>G | p.Lys3115Arg | missense_variant | 25/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251298Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135806
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461794Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 727188
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 21, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 07, 2023 | This missense variant replaces lysine with arginine at codon 3115 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 functional study has shown this variant was able to rescue Brca2-deficient mouse embryonic stem cells in sensitivity assays to DNA damaging agents (PMID: 33314489). This variant has been reported in one individual affected with breast cancer and two unaffected individuals (PMID: 33314489, 33471991; Leiden Open Variation Database DB-ID BRCA2_007522). This variant has been identified in 10/251298 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) | Sep 18, 2010 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | May 25, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 13, 2024 | This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 24, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 9572A>G; This variant is associated with the following publications: (PMID: 10923033, 31843900, 12228710) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 07, 2023 | The frequency of this variant in the general population, 0.00029 (9/30608 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported have no effect on BRCA2 mRNA splicing (PMID: 31843900 (2019)). In a large-scale breast cancer association study, the variant was observed in an unaffected individual (PMID: 33471991 (2021), ). 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. - |
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. | Apr 18, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2023 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 3115 of the BRCA2 protein (p.Lys3115Arg). This variant is present in population databases (rs276174923, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 33314489). ClinVar contains an entry for this variant (Variation ID: 52817). 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 have shown that this missense change does not substantially affect BRCA2 function (PMID: 33314489). 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. - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 18, 2023 | Variant summary: BRCA2 c.9344A>G (p.Lys3115Arg) results in a conservative amino acid change located in the BRCA2, OB3 domain (IPR015188) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251298 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.00075), allowing no conclusion about variant significance. c.9344A>G has been reported in the literature in individuals affected with breast cancer (example, Lai_2017, Sharma-Oates_2018, Casadei_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Sullivan_2021). The most pronounced variant effect results in approximately >50%-90% of normal activity and the authors concluding a neutral outcome based on 1. functionally indistinguishable from WT-BRCA2 in the mESC functional assay; 2. fully rescued the lethality of BRCA2-null-mESCs and 3. exhibited no sensitivity to 6 different DNA damaging agents. The following publications have been ascertained in the context of this evaluation (PMID: 31843900, 28222693, 35693198, 33314489). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=7; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Benign, no assertion criteria provided | research | King Laboratory, University of Washington | Sep 01, 2019 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 01, 2023 | This missense variant replaces lysine with arginine at codon 3115 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 functional study has shown this variant was able to rescue Brca2-deficient mouse embryonic stem cells in sensitivity assays to DNA damaging agents (PMID: 33314489). This variant has been reported in one individual affected with breast cancer and two unaffected individuals (PMID: 33314489, 33471991; Leiden Open Variation Database DB-ID BRCA2_007522). This variant has been identified in 10/251298 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at