13-32394671-CTT-CTTT
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong
The NM_000059.4(BRCA2):c.9257-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,607,432 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000059.4 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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BRCA2 | ENST00000380152.8 | c.9257-18_9257-17insT | intron_variant | Intron 24 of 26 | 5 | NM_000059.4 | ENSP00000369497.3 | |||
BRCA2 | ENST00000530893.7 | c.8888-18_8888-17insT | intron_variant | Intron 24 of 26 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000614259.2 | n.*1315-18_*1315-17insT | intron_variant | Intron 23 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152112Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000158 AC: 23AN: 1455320Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8AN XY: 723848
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74302
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:1
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not specified Benign:2
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. -
Variant summary: BRCA2 c.9257-10dupT alters a non-conserved nucleotide located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing, which has been confirmed by functional studies analyzing patient RNA (e.g. Houdayer_2012, Montalban_2019). The variant allele was found at a frequency of 4.6e-05 in 240598 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.9257-10dupT has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (e.g. Velasco_2005, Montalban_2019). 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 (BIC: BRCA1 c.3700_3704delGTAAA, p.Val1234_Asn1235?fs; BRCA1 c.66_67delAG, p.Leu22_Glu23LeuValfs), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 22505045, 31343793, 15937982). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Hereditary breast ovarian cancer syndrome Benign:2
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BRCA2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
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Hereditary cancer-predisposing syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at