rs762815401
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong
The NM_000059.4(BRCA2):c.6938-25_6938-19del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000038 in 1,526,286 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000041 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 intron
NM_000059.4 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.27
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 -8 ACMG points.
BP6
?
Variant 13-32346795-CTAATATG-C is Benign according to our data. Variant chr13-32346795-CTAATATG-C is described in ClinVar as [Likely_benign]. Clinvar id is 420655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32346795-CTAATATG-C is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.6938-25_6938-19del | intron_variant | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.6938-25_6938-19del | intron_variant | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151968Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000566 AC: 13AN: 229588Hom.: 0 AF XY: 0.0000401 AC XY: 5AN XY: 124746
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GnomAD4 exome AF: 0.0000408 AC: 56AN: 1374202Hom.: 0 AF XY: 0.0000364 AC XY: 25AN XY: 686654
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 12, 2020 | Variant summary: BRCA2 c.6938-25_6938-19delGTAATAT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.6e-05 in 230226 control chromosomes, predominantly at a frequency of 0.00077 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (5.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.6938-25_6938-19delGTAATAT has been reported in the literature as IVS12-25del7 in at-least one individual of Chinese ethnicity reportedly affected with benign breast disease (Suter_2004). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Since its previous evaluation as a likely benign variant at our laboratory, we have observed at-least two co-occurrences with other pathogenic variant(s) (BRCA1 c.1518delG , p.Arg507AspfsX25 and BRCA1 c.2800C>T, p.Gln934X) that could explain the phenotype in affected individuals, providing additional supporting evidence for a benign role.To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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 re-classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 16, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 09, 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. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at