13-32336595-A-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000059.4(BRCA2):āc.2240A>Gā(p.Glu747Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,998 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).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.2240A>G | p.Glu747Gly | missense_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.1871A>G | p.Glu624Gly | missense_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.2240A>G | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152236Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251276Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135816
GnomAD4 exome AF: 0.0000322 AC: 47AN: 1461762Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 32AN XY: 727178
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74376
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:2
This alteration is classified as 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. -
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
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This missense variant replaces glutamic acid with glycine at codon 747 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported that this variant does not impact BRCA2 function in the rescue of sensitivity to poly(ADP)-ribose polymerase inhibitors in BRCA2-deficient cells (PMID: 32444794). This variant has been reported in individuals affected with breast cancer (PMID: 32846166, 33552952, 37725154). This variant has been identified in 9/251276 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. -
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3
This missense variant replaces glutamic acid with glycine at codon 747 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 that the variant has neutral impact on sensitivity to PARP inhibitors (PMID: 32444794). This variant has been reported in 2 individuals affected with breast cancer (PMID: 32846166, 33552952). This variant has been identified in 9/251276 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. -
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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. -
not provided Uncertain:3
Observed in individuals with a personal history of breast and/or ovarian cancer (PMID: 33552952); Published functional studies demonstrated cell viability similar to wild-type when exposed to various PARP inhibitors (PMID: 32444794); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2468A>G; This variant is associated with the following publications: (PMID: 25722345, 32846166, 29884841, 31853058, 33552952, 32444794) -
In the published literature, this variant has been reported in individuals affected with breast and/or ovarian cancer (PMIDs: 33552952 (2020), 32846166 (2020)). Functional studies have shown that the variant results in normal sensitivity to PARP inhibitors (PMID: 32444794 (2020)), however further research is needed to understand the global impact of the variant on protein function. The frequency of this variant in the general population, 0.00029 (9/30612 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. -
The BRCA2 p.Glu747Gly variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was also identified in dbSNP (ID: rs397507283) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and three other submitters), and LOVD 3.0 (2x). The variant was identified in control databases in 9 of 246080 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5480 chromosomes (freq: 0.0002) and South Asian in 8 of 30782 chromosomes (freq: 0.0003), while the variant was not observed in the African, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Glu747 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Hereditary breast ovarian cancer syndrome Uncertain:2
This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 747 of the BRCA2 protein (p.Glu747Gly). This variant is present in population databases (rs397507283, gnomAD 0.03%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 32846166, 33552952). ClinVar contains an entry for this variant (Variation ID: 37778). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 32444794). 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. -
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not specified Uncertain:1
Variant summary: The BRCA2 c.2240A>G (p.Glu747Gly) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant, however these predictions have yet to be confirmed by functional studies. This variant was found in 9/246080 control chromosomes at a frequency of 0.0000366, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at