rs397507389

chr13-32357741-G-Achr13-32357741-G-Cchr13-32357741-G-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):c.7618-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 9.31

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 22 ACMG points.

• PVS1: Splicing 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-32357741-G-A is Pathogenic according to our data. Variant chr13-32357741-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38110.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357741-G-A is described in Lovd as [Pathogenic]. Variant chr13-32357741-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7618-1G>A		splice_acceptor_variant		ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7618-1G>A		splice_acceptor_variant		5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 09, 2010	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 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	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant causes a G to A nucleotide substitution at the -1 position of intron 15 of the BRCA2 gene. RNA studies have detected out-of-frame splicing in the RNA from carriers of this variant, resulting in premature truncation (PMID: 21394826, 22006311, 31843900). This variant has been detected in at least 4 individuals affected with breast, pancreatic and peritoneal cancer (PMID: 12097290, 22006311, 26681312, 35451682) and has been identified in 11 families among the CIMBA participants (PMID: 29446198). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 17, 2015	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 17, 2021	This variant disrupts a canonical splice-acceptor site and interferes with normal BRCA2 mRNA splicing. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 21394826 (2011), 22006311 (2011), 29881398 (2018)) and peritoneal cancer (PMID: 22006311 (2011)). Functional studies of this variant show abnormal splicing that results in a disrupted protein product (PMIDs: 21394826 (2011) and 29881398 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2022	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: causes aberrant splicing resulting in multiple transcripts, including partial deletion of exon 16 and exon 17, predicted to result in a null allele (Whiley 2011, Fraile-Bethencourt 2018); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Murphy 2002, Walsh 2011, Tung 2016); Not observed at significant frequency in large population cohorts (gnomAD); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 7846-1G>A; This variant is associated with the following publications: (PMID: 12097290, 20104584, 30832263, 21990134, 21394826, 22006311, 17924331, 25085752, 26976419, 26681312, 29881398, 24240112, 23725378, 29446198, 28492532, 31843900, 31447099, 32398771, 30787465) -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 22, 2023	This variant causes a G to A nucleotide substitution at the -1 position of intron 15 of the BRCA2 gene. RNA studies have detected out-of-frame splicing in the RNA from carriers of this variant, resulting in premature truncation (PMID: 21394826, 22006311, 31843900). This variant has been detected in at least 4 individuals affected with breast, pancreatic and peritoneal cancer (PMID: 12097290, 22006311, 26681312, 35451682) and has been identified in 11 families among the CIMBA participants (PMID: 29446198). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 21, 2022	The c.7618-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide before coding exon 15 in the BRCA2 gene. This alteration has been reported in multiple individuals with hereditary breast and/or ovarian cancer (Whiley PJ et al. Hum. Mutat. 2011 Jun;32:678-87; Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7). RNA and minigene assays have shown that this alteration results in a majority of transcript lacking 45bp from coding exon 14 (Ambry internal data; Whiley PJ et al. Hum. Mutat. 2011 Jun;32:678-87; Fraile-Bethencourt et al. Front Genet 2018 May;9:188). Of note, this alteration is also designated as IVS15-1G>A in published literature. 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 23, 2021	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change affects an acceptor splice site in intron 15 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. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer and peritoneal carcinoma (PMID: 21394826, 22006311, 26681312). This variant is also known as c.7846-1G>A and IVS15-1G>A. ClinVar contains an entry for this variant (Variation ID: 38110). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21394826, 21990134). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 21394826, 22006311; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2016	Variant summary: The BRCA2 c.7618-1G>A variant involves the alteration of a conserved intronic nucleotide with 5/5 splice prediction tools predicting a significant impact on splicing, which is functionally supported. The variant of interest has not been observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -

Hereditary breast ovarian cancer syndrome;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	35
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.78		Position offset: 45
DS_AL_spliceai		0.99		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs397507389; hg19: chr13-32931878;