rs80358744
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000059.4(BRCA2):c.5182G>A(p.Asp1728Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000935 in 1,604,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1728V) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.5182G>A | p.Asp1728Asn | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5182G>A | p.Asp1728Asn | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152058Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000411 AC: 1AN: 243070Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131550
GnomAD4 exome AF: 0.00000826 AC: 12AN: 1452350Hom.: 0 Cov.: 44 AF XY: 0.00000831 AC XY: 6AN XY: 722340
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152058Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74278
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Dec 23, 2003 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 15, 2023 | The p.D1728N variant (also known as c.5182G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5182. The aspartic acid at codon 1728 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been detected in several Japanese cohorts of selected and unselected breast and/or ovarian cancer and prostate cancer patients, as well as in some unaffected control populations (Nakamura S et al. Breast Cancer, 2015 Sep;22:462-8; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Arai M et al. J. Hum. Genet., 2018 Apr;63:447-457; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376). This amino acid position is not well conserved in available vertebrate species, and asparagine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 16, 2022 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 51808). This missense change has been observed in individual(s) with breast cancer as well as in unaffected individuals (PMID: 24249303, 29176636, 30287823). This variant is present in population databases (rs80358744, gnomAD 0.006%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1728 of the BRCA2 protein (p.Asp1728Asn). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at