chr13-32398251-C-T
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6_Very_StrongBP7
The NM_000059.4(BRCA2):c.9738C>T(p.Ala3246=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,613,924 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. A3246A) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.9738C>T | p.Ala3246= | synonymous_variant | 27/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.9738C>T | p.Ala3246= | synonymous_variant | 27/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152080Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000251 AC: 63AN: 251304Hom.: 1 AF XY: 0.000191 AC XY: 26AN XY: 135830
GnomAD4 exome AF: 0.0000561 AC: 82AN: 1461844Hom.: 1 Cov.: 31 AF XY: 0.0000495 AC XY: 36AN XY: 727222
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152080Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74300
ClinVar
Submissions by phenotype
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 05, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 24, 2017 | Variant summary: The BRCA2 c.9738C>T (p.Ala3246Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts this variant may affect binding of multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 66/277196 control chromosomes (gnomAD, Ruiz-Flores_2002), predominantly observed in the Latino subpopulation at a frequency of 0.001889 (65/34416). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. The variant was reported as a polymorphism found in three Mexican HBOC patients in literature, however without strong evidence supporting the benign classification. Multiple clinical labs have classified this variant as likely benign/benign. In one internal sample, this variant co-occurred with a pathogenic variant BRCA1 c.68_69delAG, further supporting the benign outcome. Taken together, this variant is classified as Likely Benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2014 | 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. - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 27, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 18, 2014 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 18, 2016 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Oct 29, 2003 | - - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jun 29, 2017 | Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0025 (Admixed American/Latino), derived from ExAC (2014-12-17). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 07, 2022 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at