NM_000059.4:c.5632_5634delAAC

Variant names:

• chr13-32339983-AAAC-A
• rs794727015
• NM_000059.4:c.5632_5634delAAC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.5632_5634del variant in BRCA2 is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid (p.Asn1878del). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This in-frame deletion variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.01, score threshold <0.1) (BP1_Strong met).In summary, this variant meets the criteria to be classified as a Likely benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA022758/MONDO:0012933/097

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BRCA2 NM_000059.4 conservative_inframe_deletion
• Clinical Significance: Likely benign reviewed by expert panel U:8 B:1
• Conservation: PhyloP100: 1.40

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 Likely_benign. Variant got -4 ACMG points.

• BP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5632_5634delAAC	p.Asn1878del	conservative_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.5632_5634delAAC	p.Asn1878del	conservative_inframe_deletion	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5263_5265delAAC	p.Asn1755del	conservative_inframe_deletion	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5632_5634delAAC		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000807 AC: 2 AN: 247794 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459044 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 725584

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:8 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2

Jun 02, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2

Dec 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5632_5634delAAC variant (also known as p.N1878del) is located in coding exon 10 of the BRCA2 gene. This variant results from an in-frame AAC deletion at nucleotide positions 5632 to 5634. This results in the in-frame deletion of an asparagine at codon 1878. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Aug 17, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an in-frame deletion of 1 amino acid of the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an unaffected individual (PMID: 30287823) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0246 and 0.7136, respectively (PMID: 31131967). This variant has been identified in 2/247794 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Jul 25, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.5632_5634delAAC (p.Asn1878del) 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 8.1e-06 in 247794 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5632_5634delAAC in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 193790). Based on the evidence outlined above, the variant was classified as uncertain significance. -

BRCA2-related disorder Uncertain:1

Oct 19, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.5632_5634delAAC variant is predicted to result in an in-frame deletion (p.Asn1878del). This variant was reported in individuals with breast cancer (Table S1, Momozawa et al. 2018. PubMed ID: 30287823). This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32914120-AAAC-A) and interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/193790/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial colorectal cancer type X Uncertain:1

Sep 06, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Jul 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.5632_5634del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Asn1878del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs771028475, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 193790). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

BRCA2-related cancer predisposition Benign:1

Jun 11, 2024

ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.5632_5634del variant in BRCA2 is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid (p.Asn1878del). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This in-frame deletion variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.01, score threshold <0.1) (BP1_Strong met). In summary, this variant meets the criteria to be classified as a Likely benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong). -

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: rs794727015; hg19: chr13-32914120;