rs397507922

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000059.4(BRCA2):c.7617+1G>A variant causes a splice donor, intron 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, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:17

Conservation

PhyloP100: 8.76

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.7617+1G>A		splice_donor_variant, intron_variant	Intron 15 of 26	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.7617+1G>A	splice_donor_variant, intron_variant	Intron 15 of 26	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7248+1G>A	splice_donor_variant, intron_variant	Intron 15 of 26	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.7617+1G>A	splice_donor_variant, intron_variant	Intron 14 of 25	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461518

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727074

show subpopulations

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:6

Oct 02, 2015

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2017

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 29, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1 (RNA); PM2_Supporting; PP1 -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 15, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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). -

not provided

Pathogenic:4

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PVS1, PP1:Strong, PM2, PS4:Moderate -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_very_strong, PM2, PVS1 -

Apr 08, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 breast ovarian cancer syndrome

Pathogenic:3

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 18712473, 21184276, 24123850). For these reasons, this variant has been classified as Pathogenic. -

Jul 02, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Nov 26, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Apr 04, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

BRCA2-related disorder

Pathogenic:1

May 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 18, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over