13-32326103-CTGT-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM4_SupportingBP6
The NM_000059.4(BRCA2):c.433_435del(p.Val145del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000398 in 1,608,284 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P143P) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.433_435del | p.Val145del | inframe_deletion | 5/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.433_435del | p.Val145del | inframe_deletion | 5/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 152002Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250698Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135572
GnomAD4 exome AF: 0.0000398 AC: 58AN: 1456282Hom.: 0 AF XY: 0.0000359 AC XY: 26AN XY: 724568
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 152002Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74232
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 06, 2023 | The frequency of this variant in the general population, 0.000039 (5/128808 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 29176636 (2018), 22711857 (2012), 20104584 (2010)) and in an individual with a family history of breast cancer (PMID: 21218378 (2010)). Based on the available information, we are unable to determine the clinical significance of this variant. - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 08, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 29, 2019 | This variant is associated with the following publications: (PMID: 21218378, 19941162, 20104584, 29176636, 28758972) - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jun 11, 2012 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 21, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 20, 2018 | 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 05, 2021 | Variant summary: BRCA2 c.433_435delGTT (p.Val145del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 1.2e-05 in 250698 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.433_435delGTT has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (example, Borg_2010, Carney_2010, Alsop_2012, Arai_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported in the BIC database (BRCA1 c.5207T>C, p.Val1736Ala), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They have cited the variant with a majority consensus leaning towards benign (n=1)/likely benign (n=3), and uncertain significance (n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at