rs587781422

Variant names:

• chr13-32380145-GG-TA
• rs587781422
• NM_000059.4:c.9256_9256+1delGGinsTA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.9256_9256+1delGGinsTA​(p.Gly3086*) variant causes a stop gained, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 stop_gained, splice_donor, splice_region, intron
• 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9256_9256+1delGGinsTA	p.Gly3086*	stop_gained, splice_donor_variant, splice_region_variant, intron_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9256_9256+1delGGinsTA	p.Gly3086*	stop_gained, splice_donor_variant, splice_region_variant, intron_variant		5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8887_8887+1delGGinsTA	p.Gly2963*	stop_gained, splice_donor_variant, splice_region_variant, intron_variant		1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1314_*1314+1delGGinsTA		splice_region_variant, non_coding_transcript_exon_variant	Exon 23 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*1314_*1314+1delGGinsTA		splice_donor_variant, 3_prime_UTR_variant, intron_variant	Exon 23 of 25	2		ENSP00000506251.1

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

Sep 07, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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 produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jun 09, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial cancer of breast Pathogenic:1

Jun 07, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 16, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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;