rs878853287

Positions:

• chr13-32330917-A-C
• chr13-32330917-A-G

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.682-2A>C variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.04

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]

BRCA2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32330917-A-C is Pathogenic according to our data. Variant chr13-32330917-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 267659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32330917-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.682-2A>C		splice_acceptor_variant, intron_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.682-2A>C		splice_acceptor_variant, intron_variant		5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.313-2A>C		splice_acceptor_variant, intron_variant		1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.682-2A>C		splice_acceptor_variant, intron_variant		2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Oct 02, 2015

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2022

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); Published RNA studies demonstrate abnormal splicing resulting in transcripts lacking all or part of exon 9 (Santos 2014); Identified in individuals with personal or family history of breast/ovarian cancer (Santos 2014, Peixoto 2015); Also known as 910-2A>C; This variant is associated with the following publications: (PMID: 29446198, 33159495, 24916970, 24607278) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2018

The c.682-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 8 in the BRCA2 gene. This alteration was identified in a woman with early onset breast cancer and segregated with disease in her family. In addition, this alteration was shown to result in abnormal splicing that includes two out-of-frame transcripts: one lacking exon 9 (coding exon 8), and another lacking 73 nucleotides of exon 9 (coding exon 8) (Santos C et al. J Mol Diagn, 2014 May;16:324-34). Furthermore, BRCA2 c.682-2A>G is a close-match pathogenic alteration that has been identified in 1/312 male breast cancer patients with a family history of HBOC and demonstrates a very similar aberrant splicing pattern (de Juan I et al. Fam. Cancer, 2015 Dec;14:505-13; de Garibay GR et al. Hum. Mutat., 2014 Jan;35:53-7). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2022

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30883759). ClinVar contains an entry for this variant (Variation ID: 267659). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 24607278). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 8 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AL_spliceai		1.0		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853287; hg19: chr13-32905054;