rs80359432

chr13-32338496-AAAG-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PM4_Supporting BP6_Very_Strong

The NM_000059.4(BRCA2):c.4146_4148del(p.Glu1382del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000122 in 1,609,136 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. K1381K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: BRCA2 NM_000059.4 inframe_deletion
• Clinical Significance: Benign reviewed by expert panel U:8 B:11
• Conservation: PhyloP100: 5.11

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 Benign. Variant got -7 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 13-32338496-AAAG-A is Benign according to our data. Variant chr13-32338496-AAAG-A is described in ClinVar as [Benign]. Clinvar id is 37883.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.4146_4148del	p.Glu1382del	inframe_deletion	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.4146_4148del	p.Glu1382del	inframe_deletion	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000733 AC: 18 AN: 245496 Hom.: 0 AF XY: 0.0000754 AC XY: 10 AN XY: 132570

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000139

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.0000803

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000130 AC: 189 AN: 1456934 Hom.: 0 AF XY: 0.000139 AC XY: 101 AN XY: 724372

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000591

Gnomad4 FIN exome AF: 0.000450

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000529

ClinVar

Significance: Benign

Submissions summary: Uncertain:8 Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 09, 2023	Variant summary: BRCA2 c.4146_4148delAGA (p.Glu1382del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign (class 1) in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). The variant allele was found at a frequency of 7.3e-05 in 246448 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.3e-05 vs 0.00075), allowing no conclusion about variant significance. c.4146_4148delAGA has been reported in the literature in individuals affected with Breast and Ovarian Cancer (example, Wu_2005, Bosdet_2013, Monnerat_2007, Dodova_2015, Pharoah_2000). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the UMD database and at our laboratory (UMD database, BRCA1 c.4162_4163delCA, p.Gln1388GlufsX2; Our laboratory, BRIP1 c.2010dupT , p.Glu671Ter), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Wu_2005). The most pronounced variant effect results in conflicting evidence between HDR activity (supportive of loss), nuclear localization (normal), sensitivity to mitomycin C (MMC, supportive of loss), and centrosome number (normal) with the authors concluding that functional effects alone should not be taken as definite proof for pathogenicity as there is lacking information about cosegregation and limited patient reports. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (Benign, n=3 to include the expert panel; likely benign, n=3; VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above supported by an emerging majority consensus among peers and the expert panel, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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: Clinvar: 3 labs classify as LB, 1 as VUS; ExAC: 2/6606 European chromosomes -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2019	The BRCA2 c.4146_4148delAGA; p.Glu1382del variant (rs80359432) is reported in the literature in several individuals affected with breast cancer (Dodova 2015, Monnerat 2007), although a pathogenic variant in TP53 was also found in one affected individual (Monnerat 2007). This variant is found in the general population with an overall allele frequency of 0.007% (20/276904 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 37883). This variant deletes a single glutamate residue, leaving the rest of the protein in-frame. In functional assays, this variant exhibits decreased ability to promote cell survival and homology-directed repair, though it does not induce centrosome amplification (Wu 2005). However, due to limited clinical data, the significance of the p.Glu1382del variant is uncertain at this time. References: Dodova RI et al. Spectrum and frequencies of BRCA1/2 mutations in Bulgarian high risk breast cancer patients. BMC Cancer. 2015 Jul 17;15:523. Monnerat C et al. BRCA1, BRCA2, TP53, and CDKN2A germline mutations in patients with breast cancer and cutaneous melanoma. Fam Cancer. 2007;6(4):453-61. Wu K et al. Functional evaluation and cancer risk assessment of BRCA2 unclassified variants. Cancer Res. 2005 Jan 15;65(2):417-26. -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2 Benign:3

Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 24, 2008	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 11, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 1.46E-06 -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 02, 2023	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 26183948 (2015), 17624602 (2007), and 11044354 (2000)). Functional studies have reported that this variant may have deleterious effects on BRCA2 protein function, however further studies are needed to determine the global effect of this variant on BRCA2 protein activity (PMID: 15695382 (2005)). The frequency of this variant in the general population, 0.000078 (10/127472 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2018	This variant is associated with the following publications: (PMID: 24094589, 26543556, 19941162, 15695382, 17624602, 26183948, 11044354, 24323938) -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 01, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 25, 2019	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 Benign:2

Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 14, 2020

- -

BRCA2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2023

The BRCA2 c.4146_4148delAGA variant is predicted to result in an in-frame deletion (p.Glu1382del). This variant has been reported to impair homology directed repair and exhibit hypersensitivity to mitomycin C, but did not alter centrosome amplification using in vitro assays (Guidugli L et al 2013. PubMed ID: 24323938). The c.4146_4148del variant has been reported a limited number of cases of breast cancer (Monnerat et al. 2007. PubMed ID: 17624602; Dodova RI et al 2015. PubMed ID: 26183948). This variant is reported in 0.024% of alleles in individuals of European (Finnish) descent in gnomAD and has been interpreted as uncertain, likely benign, and benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37883/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Glu1382del variant is an in-frame deletion resulting in the removal of a glutamic acid (Glu) residue at position 1382. This variant has been identified in the literature and was identified in the LOVD database, in the BIC database 5X as a variant of unknown clinical importance, and is listed in the dbSNP database (ID#: rs80359432) “with non-pathogenic allele”, however no frequency information was provided. The variant was also identified in the UMD database (1x as an "unknown variant") where it was reported as co-occurring with another pathogenic variant (BRCA1 c.4162_4163delCA (p.Gln1388GlufsX2)), increasing the likelihood that the p.Glu1382del variant does not have clinical significance. This residue is not conserved in mammals, with a different amino acid, glycine (Gly), present in opossum at this position. One functional study suggested that the variant specifically alters Rad51 binding by BRCA2, resulting in loss of DNA repair activity (Wu 2005). However, the results of other functional assays in this study, including evaluation of nuclear localization and centrosome number, were similar to wild type BRCA2 which suggests that the variant may not confer a conformational change on BRCA2 that leads to inactivation of all BRCA2 functions (Wu 2005). 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). -

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: rs80359432; hg19: chr13-32912633;