rs80359588

chr13-32329450-TGAA-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_000059.4(BRCA2):c.644_646del(p.Glu215del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,596,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E214E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: BRCA2 NM_000059.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:14
• Conservation: PhyloP100: 2.84

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 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000059.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.644_646del	p.Glu215del	inframe_deletion	8/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.644_646del	p.Glu215del	inframe_deletion	8/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00000818 AC: 2 AN: 244584 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132222

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: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000831 AC: 12 AN: 1443912 Hom.: 0 AF XY: 0.00000835 AC XY: 6 AN XY: 718900

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000729

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74358

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000340

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2013	This variant, in exon 8 of the BRCA2 gene, is denoted c.644_646delAAG at the DNA level or p.Glu215del (E215del) at the protein level. The normal sequence with the bases that are deleted in braces is: TGAAG{delAAG}CATCT. This in frame deletion of 3 base pairs results in the loss of a single Glutamic acid residue at a position that is well conserved throughout evolution, however, it is not located in a known functional domain. BRCA2 c.644_646delAAG has not, to our knowledge, been reported as a mutation or as a benign polymorphism. It has been reported in the Breast Cancer Information Core (BIC) database with unknown clinical importance. Since in frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time. Based on currently available information, we consider BRCA2 c.644_646delAAG to be a variant of unknown significance. The variant is found in BRCA1-BRCA2 panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 20, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 01, 2022	The c.644_646delAAG variant (also known as p.E215del) is located in coding exon 7 of the BRCA2 gene. This variant results from an in-frame AAG deletion at nucleotide positions 644 to 646. This results in the in-frame deletion of a glutamic acid at codon 215. This alteration has been reported in several individuals with a history of breast and/or ovarian cancer (Zhong X. et al. PLoS One. 2016 Jun;11(6):e0156789; Quezada Urban R. et al. Cancers (Basel). 2018 Sep;10(10); Abdel-Razeq H. et al. Front Oncol. 2022 Mar;12:673094). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 10, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 27, 2023	This variant causes the in-frame deletion of a single amino acid, glutamic acid 215, in the BRCA2 protein. This variant is also known as c.640_642del in the literature. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast cancer and in a suspected hereditary breast and ovarian cancer family (PMID: 27257965, 30262796, 35402282, 36601340). This variant has been identified in 2/244584 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. -

Hereditary breast ovarian cancer syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This variant, c.644_646del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Glu215del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs746887088, gnomAD 0.006%). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27257965, 30262796, 35402282). This variant has been observed to co-occur in individuals with a different variant in BRCA2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. This variant is also known as p.E213del and c.640_642del. ClinVar contains an entry for this variant (Variation ID: 52106). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 28, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 06, 2023	This variant causes an in-frame deletion of one amino acid in the BRCA2 protein. In the published literature, the variant has been reported in individuals with breast cancer or with suspected hereditary breast/ovarian cancer (PMIDs: 35402282 (2022), 30262796 (2018), and 27257965 (2016)). In addition, this variant has been reported in the somatic state in a patient with uterine leiomyosarcoma (PMID: 35454841 (2022)). The frequency of this variant in the general population, 0.0000082 (2/244584 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 25, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 01, 2023

Variant summary: BRCA2 c.644_646delAAG (p.Glu215del) 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 8.2e-06 in 244584 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.644_646delAAG has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Abdel-Rezeq_2020, Quezada Urban_2018, Zhong_2016) without strong evidence for causality. 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: 19941162, 35402282, 30262796, 27257965). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Breast Cancer Information Core (BIC) (BRCA2)

Oct 29, 2001

- -

Breast neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Nov 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80359588; hg19: chr13-32903587;