chr13-32316529-T-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.67+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000205 in 1,460,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000059.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.67+2T>C | splice_donor_variant, intron_variant | Intron 2 of 26 | 5 | NM_000059.4 | ENSP00000369497.3 | |||
BRCA2 | ENST00000530893.7 | c.-303+6T>C | splice_region_variant, intron_variant | Intron 2 of 26 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000614259.2 | n.67+2T>C | splice_donor_variant, intron_variant | Intron 1 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250582Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135566
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460612Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726674
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
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This variant was identified in a 3 year old male with autism spectrum disorder, global developmental delay, hypotonia, and plagiocephaly, as a secondary finding. It was inherited from a healthy father who's family history includes several females with breast cancer. This variant has been reported in the literature and in ClinVar as a pathogenic variant, due to association with hereditary breast/ovarian cancer. The variant alters a canonical splice site. -
A known pathogenic mutation was detected in the BRCA2 gene (c.67+2T>C). This sequence change affects a donor splice site in intron 2 of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (gnomAD). This variant has been reported in an individual and a family affected with breast/ovarian cancer (PMID: 12955716, 22798144). This variant is also known as IVS2+2T>C and 295+2T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 52163). Experimental studies have shown that this intronic change disrupts splicing and results in an mRNA product with exon 2 skipped (PMID: 22505045). Exon 2 contains the translational start site of BRCA2. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic. This variant was confirmed by Sanger sequencing . -
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Hereditary breast ovarian cancer syndrome Pathogenic:3
Variant summary: BRCA2 c.67+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Houdayer_2012). The variant allele was found at a frequency of 4e-06 in 250582 control chromosomes. c.67+2T>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example, Diez_2003, AlHannan_2019, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories and one consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
The c.67+2T>C variant in BRCA2 has been reported in at least 7 individuals affected with Hereditary Breast and Ovarian Cancer (selected references, Diez 2003 PMID: 12955716, Al Hannan 2019 PMID: 31131559, Rebbeck 2018 PMID: 29446198, Pajares 2018 PMID: 29884136). It has also been reported in ClinVar (Variation ID 52163) but was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies provide some evidence that this variant affects mRNA splicing (Houdayer 2012 PMID: 22505045, Fraile-Bethencourt 2019 PMID: 30883759). Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer syndrome. ACMG/AMP Criteria applied: PM2_supporting, PVS1, PS4_Moderate. -
This sequence change affects a donor splice site in intron 2 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs81002885, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer and/or breast cancer (PMID: 12955716, 21063910, 22798144). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS2+2T>C and 295+2T>C. ClinVar contains an entry for this variant (Variation ID: 52163). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 17011978, 22505045, 30883759). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
The variant disrupts a canonical splice site, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. -
Published functional studies demonstrate a damaging effect: results in exon 2 skipping which contains the initiator codon, unable to rescue cell viability in a complementation assay (Houdayer et al., 2012; Fraile-Bethencourt et al., 2019; Mesman et al., 2020); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Diez et al., 2003; Martinez-Ferrandis et al., 2003; Kim et al., 2012; Pajares et al., 2018; Al Hannan et al., 2019); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 295+2T>C; This variant is associated with the following publications: (PMID: 31131967, 29446198, 31131559, 14517958, 25525159, 22798144, 22505045, 12955716, 18528753, 30720243, 29884136, 33654310, 32398771, 30883759) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at