rs587781422

chr13-32380145-GG-TA

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1 PP3 PP5_Very_Strong

The NM_000059.4(BRCA2):c.9256_9256+1delinsTA variant causes a splice donor, coding sequence change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 splice_donor, coding_sequence
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.27

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 13-32380145-GG-TA is Pathogenic according to our data. Variant chr13-32380145-GG-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9256_9256+1delinsTA		splice_donor_variant, coding_sequence_variant	24/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9256_9256+1delinsTA		splice_donor_variant, coding_sequence_variant	24/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	This variant results in the deletion of part of exon 24 (c.9256_9256+1delinsTA) of the BRCA2 gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 140992). Studies have shown that this variant results in skipping of exon 24 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 07, 2017	Variant summary: The BRCA2 c.9256_9256+1delinsTA variant involves the alteration of a conserved dinucleotide sequence (GG>TA) leading to the alteration of the canonical splice site at the boundary of exon 24 and intron 24. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing. ESE finder predicts that this variant may also affect the binding site of splicing factors (SF2/ASF, SRp40). The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Nevertheless, single nucleotide substitution variants affecting the same dinucleotide sequence positions and leading to the same base substitutions (i.e. c.9256G>T and c.9256+1G>A) have been reported in the literature, and c.9256+1G>A was shown in in vitro studies (Acedo 2015) leading to protein truncation (through splice site destruction and exon skipping). Moreover, both variants were classified as pathogenic by clinical diagnostic laboratories/reputable databases. Based on these data, the variant of interest is expected to affect a canonical splice site or lead to a nonsense alteration, both causing protein truncation. In addition, at least one clinical diagnostic laboratory (Ambry Genetics) classified the variant of interest as pathogenic, though they provided no further evidence for independent evaluation. Taken together, this variant is classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2015

This pathogenic variant is denoted BRCA2 c.9256_9256+1delGGinsTA and consists of a deletion and insertion of two nucleotides at the last nucleotide of exon 24 and the +1 position of intron 24. Using alternate nomenclature, this variant would be defined as BRCA2 9484_9484+1delGGinsTA. The normal sequence, with the bases that are deleted in braces and inserted in brackets, is AACA[Gg][Ta]taat, where the capital letters are exonic and lowercase are intronic. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the currently available information, we consider BRCA2 c.9256_9256+1delGGinsTA to be a pathogenic variant. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2023

The c.9256_9256+1delGGinsTA pathogenic mutation (also known as p.G3086*), results from a GG to TA substitution spanning the last nucleotide of coding exon 23 to the first nucleotide after coding exon 23 of the BRCA2 gene. This changes the amino acid from a glycine to a stop codon at position 3086, which spans coding exons 23 and 24. In one study, the c.9256+1G>A alteration (also designated as IVS24+1G>A) was shown to produce aberrant transcripts with exon 23 skipping and premature truncation in lympocytes at the mRNA level and was detected in two individuals from a family with at least two first degree relatives with breast and/or ovarian cancer at a young ages (Claes K et al. Genes Chromosomes Cancer. 2003 Jul;37:314-20). In addition, in a separate functional study using minigene assays, the c.9256+1G>A alteration resulted in aberrant splicing, including skipping of coding exon 23 (Acedo A et al. Breast Cancer Res. 2012 May;14:R87). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 07, 2023

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587781422; hg19: chr13-32954282;