13-32363445-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000059.4(BRCA2):c.8243G>A(p.Gly2748Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.8243G>A | p.Gly2748Asp | missense_variant | Exon 18 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.7874G>A | p.Gly2625Asp | missense_variant | Exon 18 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*301G>A | non_coding_transcript_exon_variant | Exon 17 of 26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259.2 | n.*301G>A | 3_prime_UTR_variant | Exon 17 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249060Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134772
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461864Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727230
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:9
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This variant has been reported in individuals affected with breast cancer in the published literature (PMID: 24323938 (2014), 23108138 (2013), 17924331 (2007), 15026808 (2004)). Additionally, functional studies have demonstrated a damaging effect of this variant on BRCA2 protein function (PMID: 25146914 (2014), 23328489 (2013), 18451181 (2007)). Based on the available information, this variant is classified as pathogenic. -
The p.Gly2748Asp variant has been reported in the literature in 3/3590 proband chromosomes of individuals with hereditary breast and ovarian cancer and ovarian carcinoma, although no control chromosomes were tested to establish the frequency in the general population (Alsop 2012, Balia 2011, Claes 2004, Farrugia 2008, Karchin 2008, Lindor 2012, Easton 2007). The p.Gly2748 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD, BLOSUM) suggest that the p.Gly2748Asp variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant is listed in the dbSNP database (ID#:rs80359071) as coming from a "clinical source" but no frequency information was provided, and so the prevalence of this variant in the population is not known. In a study that interrogated the Myriad Genetic Laboratories database to assess the clinical significance of BRCA1/2 sequence variants, segregation studies and statistical analyses suggested the p.G2748D variant was in “favour of causality” (Easton 2007). In addition, functional studies have shown that the homologous recombination repair activity is compromised, as determined by transient overexpression of this variant protein, and that it leads to an increase in the proportion of cells undergoing aberrant centriole amplification (Balia 2011, Farrugia 2008). In summary, based 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 pathogenic role for this variant. This variant is classified as Predicted Pathogenic. -
Published functional studies demonstrate a damaging effect: decreased homology-directed repair activity, increased centrosome amplification, and inability to rescue BRCA2-deficiency (PMID: 18451181, 23108138, 23328489, 25146914, 29884841, 35736817); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (PMID: 35665744, 17924331, 21990134); Observed in multiple individuals with personal and family history consistent with pathogenic variants in this gene (PMID: 15026808, 17924331, 18451181, 25447315, 26824983); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8471G>A; This variant is associated with the following publications: (PMID: 26824983, 24504028, 25504618, 30078507, 29446198, 25447315, 19043619, 21671020, 18451181, 23108138, 25146914, 23328489, 24323938, 17924331, 25085752, 15026808, 18403564, 26269718, 29394989, 29922827, 28726806, 29988080, 30720243, 30702160, 32444794, 31447099, 32029870, 29884841, 33964450, 30787465, 33978741, 36061650, 36249907, 34906479, 28888541, 31825140, 33609447, 35665744, 35736817, 35264596, 21990134, 12228710) -
The BRCA2 c.8243G>A; p.Gly2748Asp variant (rs80359071) is reported in the literature in several individuals and families affected with breast and/or ovarian cancer (Bhaskaran 2019, Claes 2004, Easton 2007). This variant is also reported in ClinVar (Variation ID: 52535), and classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 2748 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.877). Functional analyses of the variant protein show impaired homology directed repair activity (Balia 2011, Farrugia 2008, Guidugli 2013). Based on available information, this variant is considered to be pathogenic. References: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ Balia C et al. Effect of the overexpression of BRCA2 unclassified missense variants on spontaneous homologous recombination in human cells. Breast Cancer Res Treat. 2011 Oct;129(3):1001-9. PMID: 21671020. Bhaskaran SP et al. Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients. Int J Cancer. 2019 Aug 15;145(4):962-973. PMID: 30702160. Claes K et al. BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. Br J Cancer. 2004 Mar 22;90(6):1244-51. PMID: 15026808. Easton DF et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007 Nov;81(5):873-83. PMID: 17924331. Farrugia DJ et al. Functional assays for classification of BRCA2 variants of uncertain significance. Cancer Res. 2008 May 1;68(9):3523-31. PMID: 18451181. Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 2013 Jan 1;73(1):265-75. PMID: 23108138. -
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PP3, PP5, PM1, PM2, PS3 -
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Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6Uncertain:1
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This c.8243G>A (p.Gly2748Asp) variant in the BRCA2 gene has been reported in multiple breast cancer and ovarian cancer patients [PMID 15026808, 22711857] while only observed with extremely low allele frequency in general population according to gnomad database. Glycine at amino acid position 2748 is highly conserved during evolution. Functional studies showed that this mutant causes reduced homology-directed recombination repair activity, compared to wild type [PMID:18451181, 23328489, 25146914]. Multiple in silico predictions suggest this glycine to asparatic acid change is deleterious. Based upon above evidences, this c.8243G>A (p.Gly2748Asp) variant in the BRCA2 gene is classified as pathogenic. -
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IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 -
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This missense variant replaces glycine with aspartic acid at codon 2748 in the DNA binding domain of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have found the variant protein to be defective in homology-directed DNA repair assays in mammalian and yeast cells and in corroborating assays (PMID: 18451181, 23108138, 23328489, 25146914, 29394989, 29988080, 33609447, 33978741, 35736817). This variant has been reported in at least 10 individuals and families with history of breast and/or ovarian cancer (PMID: 15026808, 18451181, 22711857, 26824983, 30078507, 30702160). This variant has been identified in 2/249060 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:5
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The p.Gly2748Asp variant in BRCA2 has been reported in at least 10 individuals w ith BRCA2-associated cancers (Claes 2014, Breast Cancer Information Core (BIC) d atabase), and it was absent from large population studies. In vitro functional s tudies provide some evidence that the p.Gly2748Asp variant may impact protein fu nction (Guidugli 2014, Spugnesi 2013). In addition, this variant was classified as Pathogenic on August 10, 2015 by the ClinGen-approved ENIGMA expert panel (Cl inVar SCV000244484.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. -
Variant summary: BRCA2 c.8243G>A (p.Gly2748Asp) results in a non-conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-06 in 252586 control chromosomes. c.8243G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and pancreatic cancer (example, Li_2018, Hu_2018, Lin_2016, Alsop_2012 and Claes_2004, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. Multiple independent functional studies demonstrated a deleterious impact by the variant resulting in impaired homologous recombination activity of BRCA2 and inability to complement the loss of cell viability in mouse embryonic stem cell-based functional assays, further supporting a disease-causing impact (Guidugli_2018, Mesman_2018, Hendriks_2014, Guidugli_2012, and Farrugia_2009). Multiple clinical diagnostic laboratories, a consortium (CIMBA) and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2748 of the BRCA2 protein (p.Gly2748Asp). This variant is present in population databases (rs80359071, gnomAD 0.002%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15026808, 17924331, 22711857). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52535). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 18451181, 21671020, 23108138, 23328489, 25146914). For these reasons, this variant has been classified as Pathogenic. -
According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose these criteria: PS3 (strong pathogenic): Ikegami 2022, Mesman 2019,... (Table 9 ClinGen ENIGMA Guidelines), PP3 (supporting pathogenic): BayesDel 0.458, PP4 (very strong pathogenic): Easton 2007: LLR 3,4 => LR: 2511 -
Hereditary cancer-predisposing syndrome Pathogenic:2
This missense variant replaces glycine with aspartic acid at codon 2748 in the DNA binding domain of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have found the variant protein to be defective in homology-directed DNA repair assays in mammalian and yeast cells and in corroborating assays (PMID: 18451181, 23108138, 23328489, 25146914, 29394989, 29988080, 33609447, 33978741, 35736817). This variant has been reported in at least 10 individuals and families with history of breast and/or ovarian cancer (PMID: 15026808, 18451181, 22711857, 26824983, 30078507, 30702160). This variant has been identified in 2/249060 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
The p.G2748D pathogenic variant (also known as c.8243G>A), located in coding exon 17 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8243. The glycine at codon 2748 is replaced by aspartic acid, an amino acid with very few similar properties. This alteration, also referred to as 8471G>A in some literature, behaves as non-functional in multiple assays including a homologous repair assay, a Brca2-null mouse embryonic stem cell complementation assay, and a PARP inhibitor assay (Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Hum. Mutat. 2014 Feb;35:151-64; Guidugli L et al. Am J Hum Genet. 2018 Feb 1;102(2):233-248; Mesman RLS et al. Genet Med. 2018 Jul 10; Ikegami M. et al. Nat Commun. 2020 May;11(1):2573). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The variant has been reported in multiple individuals with HBOC in the literature and is considered pathogenic by a multifactorial analysis model of variant interpretation which demonstrated strong co-segregation and family history scores (Rebbeck TR. Hum Mutat. 2018 May;39(5):593-620; Easton DF et al. Am J Hum Genet, 2007 Nov;81:873-83). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Gastric cancer Pathogenic:1
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Familial cancer of breast Pathogenic:1
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Computational scores
Source:
Splicing
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