13-32338208-GAAAA-GA

Variant names:

• chr13-32338208-GAAA-G
• rs80359406
• NM_000059.4:c.3858_3860delAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM4_Supporting BP6

The NM_000059.4(BRCA2):​c.3858_3860delAAA​(p.Lys1286del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000732 in 1,544,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: BRCA2 NM_000059.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:15
• Conservation: PhyloP100: 2.46
• Publications: 39 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000059.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 13-32338208-GAAA-G is Benign according to our data. Variant chr13-32338208-GAAA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 37861.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.3858_3860delAAA	p.Lys1286del	disruptive_inframe_deletion	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.3858_3860delAAA	p.Lys1286del	disruptive_inframe_deletion	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.3489_3491delAAA	p.Lys1163del	disruptive_inframe_deletion	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.3858_3860delAAA		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152014 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000869 AC: 17 AN: 195552 AF XY: 0.0000842

Gnomad AFR exome AF: 0.000894

Gnomad AMR exome AF: 0.000179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000352 AC: 49 AN: 1391884 Hom.: 0 AF XY: 0.0000349 AC XY: 24 AN XY: 688480

African (AFR) AF: 0.000890 AC: 27 AN: 30340

American (AMR) AF: 0.0000934 AC: 3 AN: 32128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23556

East Asian (EAS) AF: 0.00 AC: 0 AN: 38780

South Asian (SAS) AF: 0.00 AC: 0 AN: 76760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5456

European-Non Finnish (NFE) AF: 0.00000836 AC: 9 AN: 1076078

Other (OTH) AF: 0.000175 AC: 10 AN: 57294

GnomAD4 genome AF: 0.000421 AC: 64 AN: 152132 Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74380

African (AFR) AF: 0.00144 AC: 60 AN: 41528

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67968

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000435 Hom.: 0

Bravo AF: 0.000457

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2 Benign:2

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 25, 2009

Sharing Clinical Reports Project (SCRP)

Significance: Benign

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

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1 Benign:3

Mar 17, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27741520, 19941162, 9971877, 10717622)

Oct 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 03, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:4

Feb 20, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP1_Strong c.3858_3860del, located in exon 11 of the BRCA2 gene, consists in the deletion of 3 nucleotides, predicted to cause an in-frame deletion of 1 amino acid, p.(Lys1286del). This position is outside a (potentially) clinically important functional domain and, moreover, the SpliceAI algorithm predicts no significant impact on splicing (BP1_strong). The variant allele was found in 23/20944 alleles, with a filter allele frequency of 0.0636% at 99% confidence, within the African population in the gnomAD v2.1.1 database (non-cancer data set) (BS1). To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. In addition, it was also identified in the following databases: BRCA Exchange (Not Yet Reviewed), ClinVar (5x benign, 9x likely benign, 7xuncertain significance) and LOVD (1x benign, 1x likely benign, 2x uncertain significance). Based on the currently available information, c.3858_3860del is classified as a benign variant according to ClinGen-BRCA2 Guidelines version v1.0.0.

Sep 21, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 12, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Sep 19, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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.

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Nov 16, 2021

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Nov 21, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.3858_3860delAAA (p.Lys1286del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 7.4e-05 in 1544206 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database (v4). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075). c.3858_3860delAAA has been reported in the literature in individuals affected with breast and/or ovarian Cancer (e.g. Malone_2000, Fernandes_2016, Eygelaar_2022), but also healthy controls (e.g. Wagner_1999). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9971877, 19941162, 23056405, 10717622, 17826769, 27741520, 26933808, 33643918, 35039564). ClinVar contains an entry for this variant (Variation ID: 37861). Based on the evidence outlined above, the variant was classified as benign.

Breast and/or ovarian cancer Uncertain:1

Aug 08, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Malignant tumor of breast Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Lys1286del variant has been previously reported in the literature (Wagner 1999), and was listed 7X in the BIC database with unknown clinical significance. It is listed in the dbSNP database as coming from a “clinical source” (ID#: rs80359407) however no frequency information was provided. This is an in frame-deletion which removes amino acid, Lys, from the encoded BRCA2 protein at codon 1286, however the impact on the protein function is not known. In summary, the clinical significance of this variant cannot be determined with certainty at this time. Therefore this variant is classified as a variant of unknown significance (VUS).

Hepatoblastoma Uncertain:1

Molecular Oncology - Human Genetics Lab, University of Sao Paulo

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

BRCA2-related cancer predisposition Benign:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2-related disorder Benign:1

Aug 02, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Familial cancer of breast Benign:1

Feb 09, 2024

MGZ Medical Genetics Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG codes applied following ENIGMA VCEP rules: BS1, BP1_STR

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80359406; hg19: chr13-32912345;