rs81002814
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_000059.4(BRCA2):c.7436-14T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,609,560 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 (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 splice_polypyrimidine_tract, intron
NM_000059.4 splice_polypyrimidine_tract, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.816
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 13-32356414-T-G is Benign according to our data. Variant chr13-32356414-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 52328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32356414-T-G is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7436-14T>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7436-14T>G | splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152142Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250588Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135668
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GnomAD4 exome AF: 0.0000110 AC: 16AN: 1457418Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 725360
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152142Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74344
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:2Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Jul 21, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 02, 2023 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 03, 2022 | Variant summary: BRCA2 c.7436-14T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5 prime donor site. However, analysis of mRNA showed that this variant did not affect splicing (Whiley_2011). The variant allele was found at a frequency of 8e-06 in 250588 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7436-14T>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 25, 2017 | 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. - |
not provided Benign:2
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 c.7436-14T>G variant was identified in the literature in multiple studies with multifunctional experiments, RT-PCR, and in vitro splicing and in silico analysis with likely not pathogenic and uncertain significance predictions (Wiley 2011, Lindor 2011 and Mucaki 2011). The variant was also identified in dbSNP (ID: rs81002814) as with “other” in ClinVar (with conflicting interpretations of pathogenicity, 2 x as likely benign by Invitae and Counsyl, 1 x as uncertain significance by BIC), UMD-LSDB (1 x), BIC Database (4 x unknown clinical importance, by Myriad), databases. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 2 of 245584 chromosomes at a frequency of 0.000008 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above conflicting information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as uncertain significance. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 25, 2018 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at