chr13-32340384-T-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000059.4(BRCA2):āc.6029T>Gā(p.Val2010Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,582 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).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.6029T>G | p.Val2010Gly | missense_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.5660T>G | p.Val1887Gly | missense_variant | 11/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.6029T>G | non_coding_transcript_exon_variant | 10/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250814Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135696
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461582Hom.: 0 Cov.: 45 AF XY: 0.00000825 AC XY: 6AN XY: 727086
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 10, 2016 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Aug 24, 2012 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 31, 2023 | This missense variant replaces valine with glycine at codon 2010 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 individuals affected with breast cancer or prostate cancer, and has been reported in several unaffected individuals (PMID: 18779604, 24249303, 27658390, 29215753, 31214711, 32980694). In 2 large breast cancer case-control studies conducted in Japan and by the BRIDGES consortium, this variant was reported in 5/7051 female cases and 9/11241 female controls (OR=0.885632780741425 (0.2-2.9)) (PMID: 30287823), and in 2/60466 cases and 4/53461 controls (OR=0.442 (95%CI 0.081 to 2.414); p-value=0.429) (PMID: 33471991), respectively. This variant has been identified in 5/250814 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 09, 2023 | This missense variant replaces valine with glycine at codon 2010 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 individuals with a personal or family history of breast or ovarian cancer and in two individuals affected with esophageal cancer (PMID: 9133456,18779604, 24249303, 27658390, 29176636, 29215753, 31396961, 35681111). This variant has also been detected in breast, pancreatic, and prostate cancer case-control studies in which disease association could not be established (PMID: 30287823, 31214711, 32980694, 33471991; Leiden Open Variation Database DB-ID BRCA2_002250). This variant has been identified in 5/250814 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. - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 25, 2024 | This alteration is classified as 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. - |
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). - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 12, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 04, 2020 | Observed in individuals with breast and other cancers (Inoue 1997, Kurian 2008, Haffty 2009, Lu 2015, Nakamura 2015, Yoon 2017, Momozawa 2018, So 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.6257T>G; This variant is associated with the following publications: (PMID: 29338689, 18779604, 30415210, 30287823, 9133456, 24249303, 19491284, 26689913, 27658390, 30725392, 29215753, 31131967, 31822803, 29176636) - |
Hereditary breast ovarian cancer syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2010 of the BRCA2 protein (p.Val2010Gly). This variant is present in population databases (rs80358839, gnomAD 0.03%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer, stomach adenocarcinoma (PMID: 18779604, 19491284, 26689913, 27124784, 27658390, 29176636, 29215753, 30287823, 31907386). ClinVar contains an entry for this variant (Variation ID: 51991). 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