rs81002830

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000059.4(BRCA2):​c.68-7T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,611,588 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0025 ( 12 hom. )

Consequence

BRCA2
NM_000059.4 splice_region, intron

Scores

2
Splicing: ADA: 0.01713
2

Clinical Significance

Benign reviewed by expert panel U:3B:33

Conservation

PhyloP100: 0.456
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.57).
BP6
Variant 13-32319070-T-A is Benign according to our data. Variant chr13-32319070-T-A is described in ClinVar as [Benign]. Clinvar id is 52187.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32319070-T-A is described in Lovd as [Benign]. Variant chr13-32319070-T-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00281 (428/152318) while in subpopulation AMR AF= 0.00719 (110/15298). AF 95% confidence interval is 0.0061. There are 1 homozygotes in gnomad4. There are 251 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 12 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.68-7T>A splice_region_variant, intron_variant Intron 2 of 26 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.68-7T>A splice_region_variant, intron_variant Intron 2 of 26 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.-302-7T>A splice_region_variant, intron_variant Intron 2 of 26 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.68-7T>A splice_region_variant, intron_variant Intron 1 of 25 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.00282
AC:
429
AN:
152200
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000458
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00720
Gnomad ASJ
AF:
0.0150
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00290
Gnomad FIN
AF:
0.00659
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00223
Gnomad OTH
AF:
0.00430
GnomAD3 exomes
AF:
0.00287
AC:
712
AN:
247874
Hom.:
3
AF XY:
0.00294
AC XY:
396
AN XY:
134568
show subpopulations
Gnomad AFR exome
AF:
0.000326
Gnomad AMR exome
AF:
0.00259
Gnomad ASJ exome
AF:
0.0134
Gnomad EAS exome
AF:
0.000219
Gnomad SAS exome
AF:
0.00190
Gnomad FIN exome
AF:
0.00634
Gnomad NFE exome
AF:
0.00242
Gnomad OTH exome
AF:
0.00232
GnomAD4 exome
AF:
0.00247
AC:
3603
AN:
1459270
Hom.:
12
Cov.:
32
AF XY:
0.00244
AC XY:
1768
AN XY:
725876
show subpopulations
Gnomad4 AFR exome
AF:
0.000930
Gnomad4 AMR exome
AF:
0.00238
Gnomad4 ASJ exome
AF:
0.0134
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00201
Gnomad4 FIN exome
AF:
0.00581
Gnomad4 NFE exome
AF:
0.00218
Gnomad4 OTH exome
AF:
0.00335
GnomAD4 genome
AF:
0.00281
AC:
428
AN:
152318
Hom.:
1
Cov.:
33
AF XY:
0.00337
AC XY:
251
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.000457
Gnomad4 AMR
AF:
0.00719
Gnomad4 ASJ
AF:
0.0150
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00290
Gnomad4 FIN
AF:
0.00659
Gnomad4 NFE
AF:
0.00223
Gnomad4 OTH
AF:
0.00426
Alfa
AF:
0.00363
Hom.:
0
Bravo
AF:
0.00229
EpiCase
AF:
0.00311
EpiControl
AF:
0.00296

ClinVar

Significance: Benign
Submissions summary: Uncertain:3Benign:33
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:11
Apr 12, 2018
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: curation

IARC class based on combined odds from multifactorial likelihood analysis, thresholds for class as per Easton et al. 2007 (PMID: 17924331). Class 1 Not Pathogenic based on posterior probability of pathogenicity = 7.44x10-115. There was no evidence for increased risk of breast cancer (OR 1.03; 95%CI 0.86-1.24) from case-control analysis of 83636 individuals. Nor for a deleterious effect of the variant when co-occurring with a pathogenic variant. Quantitative splicing analysis revealed an exon 3 exclusion rate of 13% in carriers compared to 3% in controls. Exon 3 exclusion from the variant allele is estimated at 20%. -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 03, 2014
Michigan Medical Genetics Laboratories, University of Michigan
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 05, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 02, 2020
BRCAlab, Lund University
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 30, 2015
Fulgent Genetics, Fulgent Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 17, 2010
Breast Cancer Information Core (BIC) (BRCA2)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 01, 2016
Department of Medical Genetics, University Hospital of North Norway
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 30, 2014
Pathway Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 13, 2014
Counsyl
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: literature only

- -

not specified Uncertain:1Benign:5
Nov 26, 2018
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Mar 28, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple conflicting assertions about splice impact; ExAC: 0.5%(36/6594) Finnish chromosomes -

Oct 23, 2014
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 18, 2017
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1Benign:4
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 23, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The BRCA2 c.68-7T>A variant involves the alteration of a non-conserved intronic nucleotide. 2/5 splice prediction tools predict a significant impact on normal splicing. Although functional studies evaluating the splicing effect of this variant show a production of a exon 3 deletion transcript wild type control DNA also showed the production of this exon 3 deletion transcript albeit at a lesser quantitative amount (Sanz_2010 and Muller_2010). Furthermore, an additional functional study evaluating the variant of interest's effect on key aspects of BRCA2 function such homologous recombination and sensitivity to DNA damaging agents showed comparable abilities to the wild-type BRCA2. This variant was found in 282/118368 control chromosomes at a frequency of 0.0023824, which is approximately 3.2 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this variant is likely a benign polymorphism. This variant has been reported in many HBOC patients/families. It has been shown not to cosegregate with disease in two families (Santos_2014). In addition, the variant has been reported to co-occur with multiple different deleterious variants in BRCA1/2 (UMD), strongly suggesting for a benign outcome. Most of the clinical diagnostic laboratories in ClinVar have classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -

Nov 16, 2021
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 21, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

Jan 16, 2018
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4
Dec 05, 2014
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 10, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Nov 28, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jun 27, 2017
True Health Diagnostics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:3
Jun 11, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 06, 2016
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BRCA2: BP4 -

Familial cancer of breast Benign:2
Apr 25, 2014
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is found in BRCA1-BRCA2,ENDOM-HEREDIC,BR-OV-HEREDIC panel(s). -

Jan 01, 2019
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1
Apr 30, 2021
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Fanconi anemia complementation group D1 Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

BRCA2-related disorder Benign:1
Sep 26, 2019
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Malignant tumor of breast Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The c.68-7T>A variant has been identified in ~20 families (and 14 affected probands) from our laboratory with breast cancer and 82 times in the UMD-BRCA2 database. In the literature, the variant was identified in 12 of 5594 proband chromosomes from individuals with breast and ovarian cancer, although an inadequate number of control chromosomes were tested to establish the variants' frequency in the general population such that the full spectrum of benign variation may not yet been defined for this gene, and increasing the possibility that this may be a benign variant (Hilton 2002, Muller 2011, Santarosa 1999, Thirthagiri 2008). The variant was identified by the ESP project (0.0015 in EU; 0.0002 in AA), and was identified in the Exome Aggregation Consortium (ExAC) database in all populations listed (European (Non-Finnish), East Asian, African, Latino, South Asian, European (Finnish)) with an overall frequency of 0.002, suggesting this may be a low frequency variant. In addition, this variant was identified by our laboratory in one individual who was homozygous for this variant who developed bilateral breast cancer late in life and the variant was suspected to segregate (in heterozygous form) with breast cancer in two other individuals in the family. However, homozygous deleterious variants of the BRCA2 gene have been demonstrated to cause Fanconi-Anemia, which was not reported in this individual, and increasing the likelihood that this variant is benign, but this information does not rule out the possibility that this variant could have contributed to the cancer in this family. The variant is listed in dbSNP database as coming from a "clinical source" (ID#: rs81002830) and had a frequency of 0.002 in the 1000 Genomes project. This variant was identified in ClinVar (by Invitae as Likely Benign, GeneDx as Benign, Sharing clinical reports project derived from Myriad reports as Uncertain significance (as of 2012 - more recently, in a personal communication Myriad has re-classified this variant as a polymorphism), by the BIC database as Uncertain significance. The c.68-7T>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 2 of 4 different programs. However, this information is not predictive enough to rule in or out pathogenicity. Studies have shown the increased rate of exon 3 skipping for this variant (20-30%), but this has also been observed in controls (Muller 2011, Thery 2011, Sanz 2010, Vreeswijk 2009, Houdayer 2012, Santorosa 1999). The c.68-7T>A variant and two other variants located at the same nucleotide position (c.68-7delT, and one c.68-78delAA) were all found to sometimes co-occur with a pathogenic BRCA2 mutation (Muller 2011), increasing the likelihood that this variant does not have clinical significance. In the UMD database, the variant was identified as co-occurring with another pathogenic variant 9x (4x in BRCA2 with: c.1796_1800delCTTAT (p.Ser599X) or c.5130_5133delTGTA (p.Tyr1710X)). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.57
CADD
Benign
5.6
DANN
Benign
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.017
dbscSNV1_RF
Benign
0.10
SpliceAI score (max)
0.050
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.

Other links and lift over

dbSNP: rs81002830; hg19: chr13-32893207; COSMIC: COSV66457916; COSMIC: COSV66457916; API