chr13-32398356-A-G
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6_Very_StrongBP7
The NM_000059.4(BRCA2):c.9843A>G(p.Pro3281=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P3281P) 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.9843A>G | p.Pro3281= | synonymous_variant | 27/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.9843A>G | p.Pro3281= | synonymous_variant | 27/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000454 AC: 69AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000119 AC: 30AN: 251278Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135796
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461866Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 727234
GnomAD4 genome ? AF: 0.000453 AC: 69AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74428
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:3
Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
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 0.0019 (African), derived from ExAC (2014-12-17). - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Oct 29, 2003 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Feb 07, 2017 | - - |
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 16, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 24, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 06, 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
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 19, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 24, 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 | Jul 30, 2015 | - - |
not provided Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Pro3281= variant was identified in 1 of 800 proband chromosomes (frequency: 0.001) from Nigerian individuals with breast cancer, unselected for age of onset and family history (Fackenthal 2012). The variant was also identified in dbSNP (ID: rs11571832) “With Uncertain significance, other allele”, ClinVar (classified with conflicting interpretations of pathogenicity; classified as benign by GeneDx, Michigan Medical Genetics Labs (U of Michigan), Baylor Miraca Genetics Labs and Invitae; likely benign by Ambry Genetics and Emory Genetics; and uncertain significance by BIC), Clinivitae (6X), LOVD 3.0 (3X) and BIC database (1X). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, BIC Database, ARUP Laboratories, and Zhejiang Colon Cancer Database. The variant was identified in control databases in 41 of 276990 chromosomes at a frequency of 0.0001 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 33 of 24028 chromosomes (frequency: 0.001), Other in 1 of 6458 chromosomes (frequency: 0.0002), Latino in 6 of 34410 chromosomes (frequency: 0.0002), European Non-Finnish in 1 of 126516 chromosomes (frequency: 0.000008), . The p.Pro3281= variant is not expected to have clinical significance because it does not result in a change of amino acid and occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
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