rs786202485
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000059.4(BRCA2):āc.3553A>Gā(p.Thr1185Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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. T1185I) 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.3553A>G | p.Thr1185Ala | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.3553A>G | p.Thr1185Ala | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461774Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727180
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 30, 2023 | The p.T1185A variant (also known as c.3553A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3553. The threonine at codon 1185 is replaced by alanine, an amino acid with similar properties. This amino acid position is poorly conserved in available 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. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 16, 2022 | This missense variant replaces threonine with alanine at codon 1185 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. - |
BRCA2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 29, 2023 | The BRCA2 c.3553A>G variant is predicted to result in the amino acid substitution p.Thr1185Ala. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In the ClinVar database, this variant has been interpreted as 'uncertain' or 'likely benign' by outside laboratories (https://preview.ncbi.nlm.nih.gov/clinvar/variation/185827/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 19, 2023 | 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: 185827). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1185 of the BRCA2 protein (p.Thr1185Ala). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at