Variant rs81002816 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:

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 13-32346901-G-A is Pathogenic according to our data. Variant chr13-32346901-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52239.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.7007+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.7007+5G>A		splice_donor_5th_base_variant, intron_variant		5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449698

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721434

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:

9.05e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:1Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	PM2(Supporting)+PP4(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -
Pathogenic, no assertion criteria provided	research	University of Washington Department of Laboratory Medicine, University of Washington	Oct 28, 2019	Functional studies using RNA from a known carrier of this variant showed that this variant results in 70% of the BRCA2 transcript from the variant allele to have altered splicing. Cosegregation analysis of this patient's family shows a likelihood ratio of 5:1 that this variant is pathogenic (using the Thompson et al. cosegregation method [PMID 12900794] with AnalyzeMyVariant.org calculator). This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant study. Taken together with frequency and in-silico predictions this variant is considered likely pathogenic. -

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 15, 2022	BP4, PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 14, 2023	The BRCA2 c.7007+5G>A variant (rs81002816) is reported in the literature in individuals affected with breast, ovarian, and pancreatic cancer (Puccini 2022, Santonocito 2020, Tsai 2019, Zuntini 2018). This variant has also been reported in three men who did not have colon or breast cancer (Tsai 2019). This variant is also reported in ClinVar (Variation ID: 52239), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this position (c.7007+5G>C) has been reported as likely pathogenic (Parsons 2019). Functional analyses using lymphoblast cell lines demonstrate that this change can result in exon 12-13 skipping and exon 13 skipping (Casadei 2019). This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Based on available information, this variant is considered to be likely pathogenic. References: Casadei S et al. Characterization of splice-altering mutations in inherited predisposition to cancer. Proc Natl Acad Sci U S A. 2019 Dec 26;116(52):26798-26807. PMID: 31843900. Parsons MT et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019 Sep;40(9):1557-1578. PMID: 31131967. Puccini A et al. Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients. Cancers (Basel). 2022 Sep 13;14(18):4447. PMID: 36139606. Santonocito C et al. Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. Cancers (Basel). 2020 May 19;12(5):1286. PMID: 32438681. Tsai GJ et al. Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. Genet Med. 2019 Jun;21(6):1435-1442. PMID: 30374176. Zuntini R et al. Dealing With BRCA1/2 Unclassified Variants in a Cancer Genetics Clinic: Does Cosegregation Analysis Help? Front Genet. 2018 Sep 11;9:378. PMID: 30254663. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2023	Published functional studies demonstrate a damaging effect: abnormal splicing (PMID: 31843900); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7235+5G>A; This variant is associated with the following publications: (PMID: 21523855, 31131967, 30254663, 32438681, 35150867, 36139606, 31843900) -

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change falls in intron 13 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 30254663). ClinVar contains an entry for this variant (Variation ID: 52239). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 13 skipping and exon 12-13 skipping and introduces a premature termination codon (PMID: 31843900; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 24, 2024	Variant summary: BRCA2 c.7007+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a 5' splicing donor site and two predict the variant weakens this site. A functional study using lymphoblast cell lines created from patients showed the variant results in 66% full lenth transcript, with 33% transcript that skips exon 12-13 or skips exon 13 (Casadei_2019). Neither abbertant transcript was found in controls. The variant was absent in 247222 control chromosomes (gnomAD). c.7007+5G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and pancreatic cancer without strong evidence of cosegregation with disease (examples: Puccini_2022, Santonocito_2020, Tsai_2019, Zuntini_2018). In one report, three men carried the variant, all without breast or prostate cancer (Tsai_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A high-throughput functional assay categorized the variant as non-functional (Sahu_2023). The following publications have been ascertained in the context of this evaluation (PMID: 30254663, 30374176, 32438681, 31843900, 36139606, 37713444). ClinVar contains an entry for this variant (Variation ID: 52239). Based on the evidence outlined above, the variant was classified as likely 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

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2024

The c.7007+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 12 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. This alteration has been identified in multiple individuals with a personal and/or family history of BRCA2-associated disease including one individual whose tumor had loss of heterozygosity of the wildtype allele (Spearman AD et al. J Clin Oncol, 2008 Nov;26:5393-400; Zuntini R et al. Front Genet, 2018 Sep;9:378; Tsai GJ et al. Genet Med, 2019 Jun;21:1435-1442; Santonocito C et al. Cancers (Basel), 2020 May;12). RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec). Several close-match alterations that are expected to have a similar splicing profile, BRCA2 c.7007G>A and BRCA2 c.7007G>C, have been observed in multiple patients with Fanconi Anemia (Meng L et al. JAMA Pediatr. 2017 12;171(12):e173438; Barber LM et al. Br. J. Haematol. 2005 Sep;130:796-7). Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because several close-match variants are identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Jun 05, 2015

- -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.74

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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.

rs81002816

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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