13-32340561-T-G

Position:

• chr13-32340561-T-G

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.6206T>G​(p.Leu2069*) variant causes a stop gained change. 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 4.22

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 (HGNC:):

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 13-32340561-T-G is Pathogenic according to our data. Variant chr13-32340561-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 38026.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340561-T-G is described in Lovd as [Pathogenic]. Variant chr13-32340561-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6206T>G	p.Leu2069*	stop_gained	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6206T>G	p.Leu2069*	stop_gained	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5837T>G	p.Leu1946*	stop_gained	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6206T>G		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 08, 2018	The c.6206T>G (p.Leu2069*) variant in the BRCA2 gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA decay. This variant is absent from large databases of genetic variation in the general population. This variant has been reported in one patient with breast cancer (PMID 16912212). Another variant in the BRCA2 gene, c.6206delT, predicting to result in the same p.Leu2069* amino acid change, has been reported in a family affected with breast and ovarian cancer (PMID 9150172). Therefore, the c.6206T>G (p.Leu2069*) variant in the BRCA2 gene is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant changes 1 nucleotide in exon 11 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 been reported in an individual affected with breast cancer (PMID: 16912212), one unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_004908) and in four families among the CIMBA participants (PMID: 29446198). 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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 06, 2023	The BRCA2 c.6206T>G (p.Leu2069*) variant causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in an individual with breast cancer (PMID: 16912212 (2006)), and observed in a world-wide screening study of families with BRCA1 and BRCA2 pathogenic variants (PMID: 29446198 (2018)). The same p.Leu2069* amino acid change caused by a different variant (c.6206del) has also been reported in a family with breast and/or ovarian cancer (PMID: 9150172 (1997)). The c.6206T>G (p.Leu2069*) variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2022	Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Malone 2006, Rebbeck 2018); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 6434T>G; This variant is associated with the following publications: (PMID: 16912212, 9150172, 29446198, 31447099, 30787465) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Leu2069* variant was identified in a multicenter (consortia) study by CIMBA in 2 of 22702 proband chromosomes (frequency: 0.00009) from females with BRCA2 pathogenic variants, the affected individuals being Caucasian American (Rebbeck 2018). The variant was also identified in dbSNP (ID: rs80358859) as “With Pathogenic allele”, in ClinVar (classified pathogenic, reviewed by an expert panel (2016); submitters: GeneDx, Invitae, Ambry Genetics, ENIGMA, CIMBA, and 3 other laboratories), and LOVD 3.0 (1x as pathogenic). The variant was not identified in the UMD-LSDB database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.6206T>G variant leads to a premature stop codon at position 2069 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 17, 2019	The p.Leu2069X variant in BRCA2 has been reported in at least 3 individuals with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database and Sharing Clinical Reports Project). It was also absent from large population studies. This nonsense variant leads to a premature termination codon at position 2069, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300999). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 38026). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu2069*) 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). -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 27, 2022	The p.L2069* pathogenic mutation (also known as c.6206T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 6206. This changes the amino acid from a leucine to a stop codon within coding exon 10. A single nucleotide deletion resulting in a stop codon at the same position (p.L2069*) has been identified in a French family with female breast and ovarian cancer (Serova-Sinilnikova OM et al. Am. J. Hum. Genet. 1997 May; 60(5):1236-9). 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jun 22, 2021	- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.91	D
Vest4		0.90
GERP RS		4.9

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: rs80358859; hg19: chr13-32914698;