rs140556653
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_000059.4(BRCA2):c.4071A>C(p.Leu1357=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000851 in 1,609,410 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. L1357L) 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 -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.4071A>C | p.Leu1357= | synonymous_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.4071A>C | p.Leu1357= | synonymous_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000519 AC: 79AN: 152166Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000117 AC: 29AN: 247446Hom.: 0 AF XY: 0.0000823 AC XY: 11AN XY: 133606
GnomAD4 exome AF: 0.0000398 AC: 58AN: 1457126Hom.: 0 Cov.: 35 AF XY: 0.0000331 AC XY: 24AN XY: 724328
GnomAD4 genome ? AF: 0.000519 AC: 79AN: 152284Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27AN XY: 74470
ClinVar
Submissions by phenotype
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 20, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 14, 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 23, 2021 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 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 | Sep 30, 2015 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 18, 2020 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:2
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 0.0017 (African), derived from ExAC (2014-12-17). - |
Hereditary breast ovarian cancer syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Apr 11, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 23, 2016 | Variant summary: The BRCA2 c.4071A>C (p.Leu1357Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation Taster predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 18/120766 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0017599 (18/10228). This frequency is about 2.35 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 African origin. This variant was reported in BrC patients without strong evidence for causality. In addition, several clinical diagnostic laboratories have classified this variant as likely benign/benign. It was also found to co-occur with a deleterious variant BRCA2 c. c.5351dup in one sample (UMD). Taken together, this variant is classified as Benign. - |
Malignant tumor of breast Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Leu1357Leu variant was identified in 6 of 918 proband chromosomes (frequency: 0.007) from individuals or families of Nigerian descent with Breast Cancers), and was not determined in 148 control chromosomes from healthy individuals (Fackenthal 2012, Fackenthal 2005).The variant was previously identified by our laboratory in 1 individual of Black/ African descent with Breast Cancer. The variant was also identified in dbSNP (ID: rs140556653 “With benign allele”, with a minor allele frequency of 0.0006(1000 Genomes Project);in NHLBI Exome Sequencing Project (Exome Variant Server)in 10 of 4406 African Americans and 0 of 8596 European chromosomes; In Exome Aggregation Consortium (ExAC) database it was identified in 18 of 10228 Africans and not found in European (Non-Finnish), East Asian, Latino, South Asian, European (Finnish) or Other individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin.The variant was also identified in ClinVar database (classified as benign by GeneDX and as likely benign by Ambry genetics) and UMD (1X as a 3 unvalidated variant).The variant was not identified in COSMIC, LOVD, GeneInsight through the Canadian Open Genetics Repository and the BIC database The p.Leu1357Leu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site.The p.Leu1357Leu variant occurs outside of the splicing consensus sequence and 5 in silico or computational prediction software programs(SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a greater than 10% difference in splicing although this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at