rs376257217
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_000059.4(BRCA2):c.5319G>A(p.Glu1773Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 1,612,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Consequence
NM_000059.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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BRCA2 | ENST00000380152.8 | c.5319G>A | p.Glu1773Glu | synonymous_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.4950G>A | p.Glu1650Glu | synonymous_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.5319G>A | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152064Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250554Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135626
GnomAD4 exome AF: 0.0000568 AC: 83AN: 1460180Hom.: 0 Cov.: 45 AF XY: 0.0000551 AC XY: 40AN XY: 726454
GnomAD4 genome AF: 0.0000395 AC: 6AN: 152064Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74302
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:4
Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). -
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Hereditary cancer-predisposing syndrome Benign:3
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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. -
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
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not specified Benign:2
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Fanconi anemia Uncertain:1
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BRCA2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Malignant tumor of breast Benign:1
The BRCA2 c.5319G>A variant was identified in dbSNP (ID: rs376257217) as “With Likely benign allele”, Clinvitae database (likely benign by ClinVar and Invitae), the ClinVar database (likely benign by Ambry Genetics and Invitae), UMD (5x with an “unclassified variant” classification). This variant was also identified in the NHLBI GO Exome Sequencing Project in 1 of 4402 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 2 of 120574 chromosomes (freq. 0.00002) in the following populations: African in 1 of 10222 chromosomes (freq. 0.0001), European in 1 of 66222 chromosomes (freq. 0.00002), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The c.5319G>A variant is not expected to have clinical significance because it does not result in a change of amino acid (p.Glu1773Glu) and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing: this is not very predictive of pathogenicity. 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 benign role for this variant. This variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at