rs397507922

Positions:

• chr13-32356610-G-A
• chr13-32356610-G-C
• chr13-32356610-G-T

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.7617+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 8.76

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: 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 13-32356610-G-A is Pathogenic according to our data. Variant chr13-32356610-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 52362.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32356610-G-A is described in Lovd as [Pathogenic]. Variant chr13-32356610-G-A is described in Lovd as [Pathogenic]. Variant chr13-32356610-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7617+1G>A		splice_donor_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7617+1G>A		splice_donor_variant		5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461518 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jan 20, 2017	- -
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	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1 (RNA); PM2_Supporting; PP1 -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 29, 2011	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 15, 2016	Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.7436_7617del transcript (encoding predicted non-functional protein). -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change affects a donor 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 and/or ovarian cancer (PMID: 21184276, 24123850). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52362). Studies have shown that disruption of this splice site results in skipping of exon 15 and introduces a premature termination codon (PMID: 18712473, 21184276, 24123850). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2024	Canonical splice site variant demonstrated to result in skipping of exon 15 leading to a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 11389159, 21184276, 24123850); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7845+1G>A; This variant is associated with the following publications: (PMID: 26360800, 17301269, 31589614, 33754277, 25525159, 11389159, 23479189, 18712473, 21184276, 21324516, 29093764, 26833046, 29339979, 30720863, 29446198, 30702160, 31191615, 24123850, 35264596) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 04, 2023	This variant causes a G to A nucleotide substitution at the +1 position of intron 15 of the BRCA2 gene. RNA studies have shown that this variant causes skipping of exon 15, resulting in premature truncation (PMID: 11389159, 21184276, 24123850, 31191615). This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 11389159, 20927582, 21184276, 24123850, 26187060, 26360800, 26833046) or pancreatic cancer (PMID: 12097290, 17301269). 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	Sep 29, 2022	The c.7617+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been described as a Danish founder pathogenic mutation and it segregates strongly with disease in many Danish families (Thomassen M et al. Breast Cancer Res. Treat., 2011 Jul;128:179-85; de Juan Jiménez I et al. Fam. Cancer, 2013 Dec;12:767-77; Roed Nielsen H et al. Acta Oncol, 2016 Sep;55:38-44; Nielsen HR et al. Fam. Cancer, 2016 Oct;15:507-12 ). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA analyses using patient RNA and minigene assays have shown this alteration results in complete loss of exon 15 (Ambry internal data; Bergthorsson JT et al. J. Med. Genet., 2001 Jun;38:361-8; Gutiérrez-Enríquez S et al. Breast Cancer Res. Treat., 2009 Sep;117:461-5; Thomassen M et al. Breast Cancer Res. Treat., 2011 Jul;128:179-85; Fraile-Bethencourt E et al. Front Genet, 2019 May;10:503; de Garibay GR et al. Hum Mutat, 2014 Jan;35:53-7). Of note, this alteration is also designated as IVS15+1G>A and 7845+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. -

BRCA2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 2024

The BRCA2 c.7617+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant (also described as IVS15+1G>A and 7845+1G>A) has been reported in multiple individuals with hereditary breast/ovarian cancer (Bergthorsson et al. 2001. PubMed ID: 11389159; Ang et al. 2007. PubMed ID: 18006916; Thomassen et al. 2011. PubMed ID: 21184276; Deng et al. 2019. PubMed ID: 30720863), prostate cancer (Roed Nielsen et al. 2016. PubMed ID: 26360800), and pancreatic cancer (Bertelsen et al. 2019. PubMed ID: 31263571). It has also been detected in two male breast cancer patients (Ding et al. 2011. PubMed ID: 20927582; Roed Nielsen et al. 2016. PubMed ID: 26360800). Of note, this variant has been reported at elevated frequencies in the Danish population, likely due to a founder effect (Thomassen et al. 2011. PubMed ID: 21184276; Nielsen et al. 2016. PubMed ID: 26833046). RNA sequencing analysis has confirmed that this variant disrupts the canonical splice donor site and leads to exon 15 skipping in ~92% of mutant mRNAs (Thomassen et al. 2011. PubMed ID: 21184276). This variant has not been reported in the gnomAD database and is interpreted as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52362/). Taken together, this variant is interpreted as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		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: rs397507922; hg19: chr13-32930747;