rs876659222
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_000059.4(BRCA2):c.7426_7428delGAA(p.Glu2476del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,648 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E2476E) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7426_7428delGAA | p.Glu2476del | conservative_inframe_deletion | Exon 14 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.7057_7059delGAA | p.Glu2353del | conservative_inframe_deletion | Exon 14 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.7426_7428delGAA | non_coding_transcript_exon_variant | Exon 13 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250980Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135700
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461436Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727026
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74358
ClinVar
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Uncertain:3
The BRCA2 c.7426_7428del (p.Glu2476del) change has a maximum subpopulation frequency of 0.004% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/13-32929409-TGAA-T?dataset=gnomad_r2_1). It is absent in a database of women older than 70 years of age who have never had cancer (https://whi.color.com/). The change results in the deletion of a single glutamic acid residue in the FANCD2 binding domain (PM4). This variant has been reported in an individual with early-onset breast cancer (PMID: 28947987). To our knowledge, functional studies have not been performed for this variant. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, PM4. -
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This variant, c.7426_7428del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Glu2476del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs757707698, gnomAD 0.004%). This variant has been observed in individual(s) with breast cancer (PMID: 27463008, 28947987, 35264596, 35534704). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 provided Uncertain:2
In-frame deletion of 1 amino acid(s) in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7654del3, 7654_7656del, and c.7420_7422del: p.2474_2474del; This variant is associated with the following publications: (PMID: 35264596, 25479140, 25085752, 27463008, 28947987, 35534704, 39400928) -
The BRCA2 c.7426_7428del (p.Glu2476del) variant has been reported in the published literature in affected individuals with breast cancer (PMIDs: 27463008 (2016), 28947987 (2017), 35264596 (2022), and 35534704 (2022)). The frequency of this variant in the general population, 0.0000071 (2/282382 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -
Hereditary cancer-predisposing syndrome Uncertain:2
This variant cause an in-frame deletion of one amino acid, glutamic acid 2476, in the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer (PMID: 28947987; Color internal data) and an individual affected with pancreatic cancer (PMID: 25479140). This variant has been identified in 2/282382 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. -
The c.7426_7428delGAA variant (also known as p.E2476del) is located in coding exon 13 of the BRCA2 gene. This variant results from an in-frame GAA deletion at nucleotide positions 7426 to 7428. This results in the in-frame deletion of a glutamic acid at codon 2476. This alteration was identified in one proband from a cohort of Argentine cohort of 940 families with breast and/or ovarian cancer (Solano AR et al. Oncotarget, 2017 Sep;8:60487-60495) and in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not specified Uncertain:1
Variant summary: BRCA2 c.7426_7428delGAA (p.Glu2476del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4e-06 in 250980 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7426_7428delGAA has been reported in the literature in individuals affected with breast cancer and pancreatic cancer (eg., Grant_2015, Guindalini_2022, Solano_2017, de Oliveira_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been reported in a patient with breast cancer (BRCA1 c.5074+2T>C), providing supporting evidence for a benign role (e.g., de Oliveira_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25479140, 35264596, 28947987, 35534704). ClinVar contains an entry for this variant (Variation ID: 231555). 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
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Familial cancer of breast Uncertain:1
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Breast-ovarian cancer, familial, susceptibility to, 2 Benign:1
This variant is considered likely 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]. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at