Variant 13-32354859-A-T details in Genebe, Genetics Data Aggregator

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:

BRCA2 (HGNC:):

BRCA2 links:

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 13-32354859-A-T is Pathogenic according to our data. Variant chr13-32354859-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 52246.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32354859-A-T is described in Lovd as [Pathogenic]. Variant chr13-32354859-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.7008-2A>T		splice_acceptor_variant, intron_variant		ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.7008-2A>T	splice_acceptor_variant, intron_variant	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 linkuse as main transcript	c.6639-2A>T	splice_acceptor_variant, intron_variant	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 linkuse as main transcript	n.7008-2A>T	splice_acceptor_variant, intron_variant	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1399800

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699986

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:

0.00

Gnomad4 NFE exome

AF:

9.47e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:5

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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 05, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The c.7008-2A>T variant has been previously reported in the literature in 8/64 proband chromosomes of individuals of Italian descent with hereditary breast and/or ovarian cancer. However, no control chromosomes were evaluated to establish the prevalence of the variant in the general population (Colombo 2009, Pensabene 2009, Lowery 2011, Gaildrat 2012, Diez 2009). Interestingly, the authors of the above studies reported that this particular mutation was found to co-exist with another BRCA2 variant, c.631G>A, a co-occurrence that we have also observed in this individual. The c.7008-2A>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the -2 position of the splice consensus sequence. Indeed, functional studies have shown that the variant altered the natural splice sites leading to exon skipping due to modification of the 5' splice site (Pensabene 2009, Gaildrat 2012). In-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in all 5 programs. The variant has been reported twice in the UMD database as causal, and six times in the BIC database as clinically significant. However, as one of the studies pointed out, the c.7008-2A>T mutation may not contribute to cancer risk in the context of the c.631G>A variant, since it lies downstream of the other mutation identified in this individual that completely abolishes the synthesis of a functional gene product (Colombo 2009). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 03, 2016	Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.7008_7435del, r.7008_7017del, and r.7008_7253del transcripts (encoding predicted non-functional proteins). -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 22, 2021	This variant is located in a canonical splice-acceptor site and interferes with normal BRCA2 mRNA splicing. In the published literature, the variant has been reported in patients with hereditary breast and ovarian cancer, male breast cancer, prostate cancer, and pancreatic cancer (PMIDs: 32854451 (2020), 32338768 (2020), 32058061 (2020), 32438681 (2020), 33287145 (2020), 31512090 (2019), 31336956 (2019), 30014164 (2018), 25980754 (2015), 21934105 (2011), 19179552 (2009), 19423647 (2009)). In functional studies, this variant has been shown to disrupt splicing and lead to exon skipping (PMIDs: 30883759 (2019), 26913838 (2016), 23451180 (2013), 22962691 (2012), 22505045 (2012)). Of note, this variant is frequently reported in cis with BRCA2 c.631G>A (p.Val211Ile), also reported in the literature as c.859G>A (PMIDs: 32338768 (2020), 32058061 (2020), 32438681 (2020), 33287145 (2020), 31336956 (2019), 19423647 (2009), 19179552 (2009), 12960223 (2003)). It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2023	Canonical splice site variant demonstrated to result in aberrant splicing, producing multiple out-of-frame transcripts in a gene for which loss-of-function is a known mechanism of disease (Pensabene et al., 2009; Colombo et al., 2009; Colombo et al., 2013; Houdayer et al., 2012; Fraile-Bethencourt et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 7236-2A>T; This variant is associated with the following publications: (PMID: 30014164, 19179552, 19423647, 21934105, 22962691, 22505045, 27125725, 29446198, 31191615, 32398771, 32438681, 31336956, 31512090, 31209999, 32854451, 33287145, 33810291, 32338768, 25525159, 23451180, 33804961, 35411189, 30613976, 32853339) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 23, 2022	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 27, 2024	ONLY INCLUDE IF PT HAS BOTH c.7008-2A>T and c.631G>A (p.V211I) BRCA2 VARIANTS The c.631G>A pathogenic mutation (also known as p.V211I), located in coding exon 6 of the BRCA2 gene, results from a G to A substitution at nucleotide position 631. The amino acid change results in valine to isoleucine at codon 211, an amino acid with highly similar properties; however, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. The c.7008-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides before coding exon 13 in the BRCA2 gene. The c.631G>A and c.7008-2A>T alterations have been identified in cis in multiple individuals and families with HBOC (Gaildrat PJ et al. Med. Genet. 2012 Oct;49(10):609-17; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4). These alterations have also been identified in cis in one individual with pancreatic adenocarcinoma (Lowery MA et al. Oncologist 2011;16(10):1397-402). Functional studies have demonstrated that the c.631G>A alteration leads to the skipping of coding exon 6, leading to a frameshift and alternate stop in coding exon 8 (Ambry internal data; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4). Functional studies have also demonstrated that the c.7008-2A>T alteration leads to multiple frameshifting aberrant transcripts which may be incomplete (Ambry internal data; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4; Houdayer C et al. Hum. Mutat. 2012 Aug;33(8):1228-38; Colombo M et al. PLoS ONE 2013;8(2):e57173). Of note, c.631G>A and c.7008-2A>T are also designated as 859G>A and IVS13-2A>T, respectively, in published literature. Based on the available evidence, c.631G>A and c.7008-2A>T are classified as a pathogenic haplotype. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 03, 2021	This variant is predicted to abolish the intron 13 splice acceptor site of the BRCA2 gene. RNA studies using patient-derived cells have shown that this variant causes skipping of exon 14 and premature truncation but does not completely abolish normal RNA splicing (thus referred to as a "leaky" splice variant) (PMID: 19179552, 19423647, 23451180) and causes aberrant splicing in minigene splicing assay (PMID: 31191615). This variant has been reported in an individual affected with ductal carcinoma in situ (PMID: 30014164). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. This variant also has been reported to co-occur with a pathogenic splice variant c.631G>A in the BRCA2 gene in at least seven unrelated European individuals affected with breast/ovarian cancer (PMID: 19179552, 19423647, 23451180, 27125725, 31336956) and in an individual affected with pancreatic adenocarcinoma (PMID: 21934105). In six of the individuals affected with breast/ovarian cancer, these variants were reported to occur on the same chromosome (in cis phase) determined in part by retro-transcription analysis or segregation analysis in family studies (PMID: 19179552, 19423647, 22962691, 31336956). For several individuals who carried both variants (PMID: 21934105; Color internal data), the phase of the two variants has not been determined. These two variants have not been reported in trans in the literature. Therefore, although this test cannot distinguish if c.631G>A and c.7008-2A>T variants occur on the same chromosome (in cis) or on opposite chromosomes (in trans), it is likely that these variants are in cis when found together in an individual. -

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2023	This sequence change affects an acceptor splice site in intron 13 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 a personal or family history of BRCA2-related conditions. In some cases, this variant occurred on the same chromosome as the c.631G>A (p.Val211Ile) variant (PMID: 19179552, 19423647, 22962691, 25980754, 29446198, 30014164). This variant is also known as IVS13-2A>T. ClinVar contains an entry for this variant (Variation ID: 52246). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 19179552, 22505045, 23451180, 31191615; Invitae). 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	Aug 17, 2023	Variant summary: BRCA2 c.7008-2A>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four out of four predict the variant abolishes a 3' canonical acceptor site. Multiple studies report experimental evidence that this variant affects mRNA splicing (e..g, Pensabene_2009, Colombo_2009, Houdayer_2012). The variant was absent in 250362 control chromosomes. c.7008-2A>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Azzollini_2016, Colombo_2009, Diez_2009, Gaildrat_2012, Pensabene_2009, Saied_2021). These data indicate that the variant is very likely to be associated with disease. The variant has been reported in several studies to co-occur with another splice mutation c.631G>A, likely on the same allele. The following publications have been ascertained in the context of this evaluation (PMID: 27062684, 23451180, 19423647, 19542536, 22962691, 22505045, 19179552, 34296289). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic or likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

- -

Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

GERP RS

5.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: 12

DS_AL_spliceai

0.97

Position offset: 2

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.

13-32354859-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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