13-32338208-GAAAA-GA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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:14
• Conservation: PhyloP100: 2.46

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 id is 37861.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Benign=4, Uncertain_significance=4}.

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

GnomAD3 exomes AF: 0.0000869 AC: 17 AN: 195552 Hom.: 0 AF XY: 0.0000842 AC XY: 9 AN XY: 106940

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 SAS 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

Gnomad4 AFR exome AF: 0.000890

Gnomad4 AMR exome AF: 0.0000934

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: 0.00000836

Gnomad4 OTH exome AF: 0.000175

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

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

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:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

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

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 25, 2009

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:3

Jan 13, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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) -

Nov 03, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3

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. -

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

- -

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

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. -

Nov 21, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs80359406; hg19: chr13-32912345;