Variant rs794727015 details in Genebe, Genetics Data Aggregator

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 inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign reviewed by expert panel U:7B:1

Conservation

PhyloP100: 1.40

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]

BRCA2 links:

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ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.5632_5634del	p.Asn1878del	inframe_deletion	11/27	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.5632_5634del	p.Asn1878del	inframe_deletion	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000807

AC:

AN:

247794

Hom.:

AF XY:

0.00000747

AC XY:

AN XY:

133864

show subpopulations

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:

AN:

1459044

Hom.:

AF XY:

0.00000413

AC XY:

AN XY:

725584

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

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.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:7Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 02, 2019	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 17, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 29, 2023	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 25, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 19, 2022

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. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

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

Likely benign, reviewed by expert panel

curation

ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen

Jun 11, 2024

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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over