13-32332889-G-T

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.1411G>T(p.Glu471Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. E471E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: -0.283

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 13-32332889-G-T is Pathogenic according to our data. Variant chr13-32332889-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 51120.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332889-G-T is described in Lovd as [Pathogenic]. Variant chr13-32332889-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.1411G>T	p.Glu471Ter	stop_gained	10/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.1411G>T	p.Glu471Ter	stop_gained	10/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Aug 15, 2017	This c.1411G>T (p.Glu471*) variant in the BRCA2 gene has been reported in three individuals with breast cancer in the Breast Cancer Information Core (BIC) database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on the current evidence, the c.1411G>T (p.Glu471*) variant in the BRCA2 gene is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 15, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2021	Nonsense 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; Observed in a woman with ovarian cancer (Carter 2018); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1639G>T; This variant is associated with the following publications: (PMID: 30322717, 26681312, 26023681, 29446198, 31447099) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 21, 2020	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals with personal history of ovarian cancer and others with family history of hereditary breast and ovarian cancer in the published literature (PMID: 30322717 (2018), 29446198 (2018), 26681312 (2015), 26023681 (2015)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant changes 1 nucleotide in exon 10 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 24, 2021	The p.E471* pathogenic mutation (also known as c.1411G>T), located in coding exon 9 of the BRCA2 gene, results from a G to T substitution at nucleotide position 1411. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation was identified in a cohort of 4439 women with ovarian cancer undergoing multigene panel testing at one laboratory (Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488). This mutation has also been reported in other cohorts of individuals who underwent BRCA1/2 analysis (Foley SB et al. EBioMedicine, 2015 Jan;2:74-81; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). 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:2

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	This sequence change creates a premature translational stop signal (p.Glu471*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 26681312). This variant is also known as c.1638G>T and 1639G>T. ClinVar contains an entry for this variant (Variation ID: 51120). For these reasons, this variant has been classified as Pathogenic. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.19	N
MutationTaster	Benign	1.0	A;A
Vest4		0.82
GERP RS		-0.84

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: rs80358428; hg19: chr13-32907026;