13-32379396-A-G
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000059.4(BRCA2):c.8834A>G(p.Gln2945Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000185 in 1,461,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.8834A>G | p.Gln2945Arg | missense_variant | Exon 22 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.8465A>G | p.Gln2822Arg | missense_variant | Exon 22 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*892A>G | non_coding_transcript_exon_variant | Exon 21 of 26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259 | n.*892A>G | 3_prime_UTR_variant | Exon 21 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250798Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135562
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461556Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 727074
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Uncertain:3
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The BRCA2 c.8834A>G (p.Gln2945Arg) variant has not been reported in individuals with BRCA2-related conditions in the published literature. The frequency of this variant in the general population, 0.000035 (4/113334 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. -
This variant is denoted BRCA2 c.8834A>G at the cDNA level, p.Gln2945Arg (Q2945R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). Using alternate nomenclature, this variant would be defined as BRCA2 9062A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln2945Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Gln2945Arg occurs at a position that is not conserved and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Gln2945Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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Hereditary cancer-predisposing syndrome Uncertain:2
The p.Q2945R variant (also known as c.8834A>G), located in coding exon 21 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8834. The glutamine at codon 2945 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is 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. -
This missense variant replaces glutamine with arginine at codon 2945 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 1.8339, respectively (PMID: 31131967). This variant has been identified in 4/250798 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. -
not specified Uncertain:1
Variant summary: BRCA2 c.8834A>G (p.Gln2945Arg) results in a conservative amino acid change located in the OB2 domain (Yang_2002) of 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 1.6e-05 in 250798 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8834A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.4183C>T (p.Gln1395X) from UMD database, an unspecified BRCA1 variant from a clinical diagnostic laboratory), providing supporting evidence for a benign role. The following publication has been ascertained in the context of this evaluation (PMID: 12228710). ClinVar contains an entry for this variant (Variation ID: 141506). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
BRCA2-related cancer predisposition Uncertain:1
This missense variant replaces glutamine with arginine at codon 2945 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 1.8339, respectively (PMID: 31131967). This variant has been identified in 4/250798 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. -
Fanconi anemia complementation group D1 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Familial cancer of breast Uncertain:1
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Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 2945 of the BRCA2 protein (p.Gln2945Arg). This variant is present in population databases (rs587781800, gnomAD 0.004%). 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: 141506). 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%. 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