rs397507884
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000059.4(BRCA2):c.681+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000059.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.681+4A>G | splice_region_variant, intron_variant | Intron 8 of 26 | 5 | NM_000059.4 | ENSP00000369497.3 | |||
BRCA2 | ENST00000530893.7 | c.312+4A>G | splice_region_variant, intron_variant | Intron 8 of 26 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000614259.2 | n.681+4A>G | splice_region_variant, intron_variant | Intron 7 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 27
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant causes an A>G nucleotide substitution at the +4 position of intron 8 of the BRCA2 gene. This variant may cause an intronic cryptic donor be used which inserted 4 nucleotides downstream from 5′ splice site shown in RNA extracted from patient derived lymphoblastoid cell lines and minigene assay (PMID: 22505045, 30883759). This variant has been reported in at least 1 individual underwent genetic testing for BRCA1 and BRCA2 based on individual and/or family history (PMID: 22505045) and two individuals with breast cancer and/or ovarian cancer in UMD database. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -
The c.681+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 7 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Splicing studies from both human lymphoblastoid cell lines and minigene show that this variant results in use of the predicted alternate donor site leading to a frameshift with predicted premature truncation (Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38; Fraile-Bethencourt E et al. J. Pathol., 2019 Aug;248:409-420). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Variant summary: BRCA2 c.681+4A>G alters a 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: Four predict the variant abolishes/weakens a 5' donor site. Four predict the variant strengthens a cryptic intronic 5 donor site. These predictions were confirmed by experimental evidence demonstrating the variant to improve an intronic cryptic donor site resulting in the insertion of 4 nucleotides which causes a frameshift (p.N228Vfs*11) (Fraile-Bethencourt_2019, Houdayer_2012). The variant was absent in 237674 control chromosomes (gnomAD). c.681+4A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018). These data indicate that the variant is likely associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic (1x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change falls in intron 8 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with personal and/or family history of breast cancer (PMID: 22762150, 29446198). This variant is also known as IVS8+4A>G. ClinVar contains an entry for this variant (Variation ID: 52193). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22505045, 30883759). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1
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not provided Pathogenic:1
The BRCA2 c.681+4A>G variant has been reported in the published literature in at least one individual with personal and/or family history of breast cancer (PMIDs: 22762150 (2012)). Splicing studies predict an alternate donor site leads to a frameshift with premature truncation, resulting in loss of protein expression (PMIDs:30883759 (2019), 26913838 (2016), and 22505045 (2012)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA2 mRNA splicing. Based on the available information, this variant is classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at