rs398122736
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000059.4(BRCA2):c.1966A>G(p.Thr656Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,603,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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. T656I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.1966A>G | p.Thr656Ala | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.1966A>G | p.Thr656Ala | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152264Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000822 AC: 2AN: 243408Hom.: 0 AF XY: 0.0000152 AC XY: 2AN XY: 131432
GnomAD4 exome AF: 0.0000207 AC: 30AN: 1451410Hom.: 0 Cov.: 32 AF XY: 0.0000153 AC XY: 11AN XY: 721184
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74388
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2022 | The p.T656A variant (also known as c.1966A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1966. The threonine at codon 656 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well 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. - |
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 | Color Diagnostics, LLC DBA Color Health | Feb 28, 2023 | This missense variant replaces threonine with alanine at codon 656 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 been reported in an individual with a personal or family history of breast and/or ovarian cancer (PMID: 21120943). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002974). This variant has been identified in 2/243408 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. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 09, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 18, 2023 | Variant summary: BRCA2 c.1966A>G (p.Thr656Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 243408 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1966A>G has been reported in the literature in individuals affected with breast- and/or ovarian cancer (e.g. Caux-Moncoutier_2011, Dorling_2021), but was also found in controls (Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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: 21120943, 25348012, 33471991). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Apr 10, 2013 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 14, 2020 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one individual undergoing BRCA1/2 testing (Caux-Moncoutier 2011); Also known as 2194A>G; This variant is associated with the following publications: (PMID: 21120943) - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2023 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 656 of the BRCA2 protein (p.Thr656Ala). This variant is present in population databases (rs398122736, gnomAD 0.0009%). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 21120943). ClinVar contains an entry for this variant (Variation ID: 91765). 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 with a negative predictive value of 95%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at