rs28897704
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6_Very_StrongBP7
The NM_000059.4(BRCA2):c.627C>A(p.Leu209=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,590,474 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 Likely benign (★★★). Synonymous variant affecting the same amino acid position (i.e. L209L) 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.627C>A | p.Leu209= | synonymous_variant | 7/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.627C>A | p.Leu209= | synonymous_variant | 7/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152128Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250814Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135534
GnomAD4 exome AF: 0.0000473 AC: 68AN: 1438346Hom.: 0 Cov.: 30 AF XY: 0.0000460 AC XY: 33AN XY: 716838
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152128Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74314
ClinVar
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Mar 14, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 14, 2016 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 15, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 21, 2017 | Variant summary: The BRCA2 c.627C>A (p.Leu209Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool (Mutationtaster) predicts a damaging outcome for this variant, while 5/5 splice prediction tools via Alamut predict no significant impact on splice donor and acceptor sites, which was confirmed by an in vitro (minigene) study (Giacomo_2013). The authors noted that the variant was obtained by PCR amplification from patients genomic DNA, however, no clinical information about the patients, or information about co-segregation and co-occurrence was provided, so from this occurrence we can infer no evidence for pathogenicity. ESE finder predicts that this variant may affect multiple ESE sites; however, these predictions have yet to be confirmed by functional studies. This variant was found in 4/121164 control chromosomes, exclusively occurring in the Non-Finnish subcohort of the ExAC project (in 4/66622 control chromosomes) at an allele frequency of 0.006% which does not exceed the maximal expected allele frequency of a disease causing BRCA2 allele (0.075%). Additionally, 2 co-occurrences with possibly pathogenic BRCA2 variants listed in the UMD database (c.9609C>G (p.Tyr3203X) and c.4398_4402delACATT (p.Leu1466PhefsX2)) further support the variant to be benign. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 18, 2015 | This variant is associated with the following publications: (PMID: 23983145) - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 09, 2015 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 24, 2016 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 20, 2021 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:2
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | - - |
Likely 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 result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at