rs276174825

Positions:

• chr13-32319268-ACT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.262_263del​(p.Leu88AlafsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 0.467

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32319268-ACT-A is Pathogenic according to our data. Variant chr13-32319268-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 51317.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32319268-ACT-A is described in Lovd as [Pathogenic]. Variant chr13-32319268-ACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.262_263del	p.Leu88AlafsTer12	frameshift_variant	3/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.262_263del	p.Leu88AlafsTer12	frameshift_variant	3/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jul 16, 2010	- -
Pathogenic, no assertion criteria provided	case-control	Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	May 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 490_491del; This variant is associated with the following publications: (PMID: 28127413, 15146557, 25072261, 22923021, 33754277, 26843898, 23683081, 24578176, 20151322, 18627636, 26187060, 25940717, 26026974, 21614564, 29940740, 28724667, 28993434, 30702160, 30093976, 31825140, 30875412, 30787465, 31853058, 36385461, 36367610, 36135357, 35864222, 38003901, 38922859) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 31, 2023	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28724667 (2017), 26026974 (2015), 20151322 (2010), 18627636 (2008), and 15146557 (2004)), as well as pancreatic cancer (PMID: 25940717 (2015) and 25072261 (2014)). Based on the available information, this variant is classified as pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Apr 02, 2020

- -

Breast and/or ovarian cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 06, 2023

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2020

The c.262_263delCT pathogenic mutation, located in coding exon 2 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 262 to 263, causing a translational frameshift with a predicted alternate stop codon (p.L88Afs*12). This mutation has been identified in multiple breast, ovarian, and/or pancreatic cancer families in the literature from diverse populations (Gorski B et al. Int J Cancer. 2004 Jul 10;110(5):683-6; Thirthagiri E et al. Breast Cancer Res. 2008;10(4):R59; Novakovic S et al. Int J Oncol. 2012 Nov;41(5):1619-27; Blay P et al. BMC Cancer. 2013 May 17;13:243; Holter S et al. J. Clin. Oncol. 2015 Oct;33(28):3124-9; de Juan I et al. Fam. Cancer 2015 Dec;14(4):505-13; Wen WX et al. J. Med. Genet.,2018 02;55:97-103; Chan GHJ et al. Oncotarget. 2018 Jul;9:30649-30660; Bhaskaran SP et al. Int. J. Cancer. 2019 08;145:962-973). Of note, this alteration is also designated as 490delCT and 488delCT in some published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 51317). This variant is also known as 488delCT and 490delCT. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15146557, 20151322, 23683081, 24578176, 25940717). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu88Alafs*12) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). -

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: rs276174825; hg19: chr13-32893405;