rs80359442
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM4_SupportingBP6
The NM_000059.4(BRCA2):c.433_435delGTT(p.Val145del) variant causes a conservative 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).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 conservative_inframe_deletion
NM_000059.4 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.603
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 Uncertain_significance. Variant got 0 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_000059.4. Strenght limited to Supporting due to length of the change: 1aa.
BP6
Variant 13-32326103-CTGT-C is Benign according to our data. Variant chr13-32326103-CTGT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37895.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=2}. Variant chr13-32326103-CTGT-C is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
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BRCA2 | NM_000059.4 | c.433_435delGTT | p.Val145del | conservative_inframe_deletion | 5/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.433_435delGTT | p.Val145del | conservative_inframe_deletion | 5/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.64_66delGTT | p.Val22del | conservative_inframe_deletion | 5/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.433_435delGTT | non_coding_transcript_exon_variant | 4/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152002Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250698Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135572
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GnomAD4 exome AF: 0.0000398 AC: 58AN: 1456282Hom.: 0 AF XY: 0.0000359 AC XY: 26AN XY: 724568
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GnomAD4 genome AF: 0.0000395 AC: 6AN: 152002Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74232
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 07, 2024 | The BRCA2 c.433_435del (p.Val145del) variant has been reported in the published literature in individuals with breast cancer (PMID: 20104584 (2010), 34597585 (2021)) and ovarian cancer (PMID: 34326862 (2021)). This variant has also been identified in a reportedly healthy individual with family history of breast cancer (PMID: 21218378 (2010)). The frequency of this variant in the general population, 0.000039 (5/128808 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. - |
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) - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 08, 2021 | - - |
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. - |
BRCA2-related cancer predisposition Benign:1
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 30, 2024 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at