13-32336764-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.2409T>G(p.Tyr803Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,192 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y803Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 0.469

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 13-32336764-T-G is Pathogenic according to our data. Variant chr13-32336764-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 37784.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32336764-T-G is described in Lovd as [Pathogenic]. Variant chr13-32336764-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.2409T>G	p.Tyr803Ter	stop_gained	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.2409T>G	p.Tyr803Ter	stop_gained	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460192 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4 AN XY: 726340

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5

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, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 21, 2011	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Tyr803X variant was identified in the literature in an individual with invasive ovarian cancer (Zhang 2011). The variant was also identified in dbSNP (ID: rs80358504) “With pathogenic allele”, HGMD, and the BIC database (1X with clinical importance). The p.Tyr803X variant leads to a premature stop codon at position 803, 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. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 30, 1999	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 14, 2022	Variant summary: BRCA2 c.2409T>G (p.Tyr803X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248736 control chromosomes. c.2409T>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Hondow_2011, Zhang_2011, Rebbeck_2018, Hollis_2020). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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	Jan 10, 2024	This sequence change creates a premature translational stop signal (p.Tyr803*) 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: 21324516, 22711857). ClinVar contains an entry for this variant (Variation ID: 37784). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2019	The p.Tyr803X variant in BRCA2 has been reported in at least 2 individuals with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database, Zhang 2011) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 803, 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 SCV000300516.2). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2022	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 3 individuals affected with ovarian cancer, 1 individual affected with breast cancer (PMID: 21324516, 22711857, 33808557, Color internal data), and has been identified in 4 families among the CIMBA participants (PMID: 29446198). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 1/53461 controls (OR=0.884. 95%CI 0.055 to 14.136; p-value=1) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_00436). 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	Jul 04, 2023	The p.Y803* pathogenic mutation (also known as c.2409T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 2409. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This alteration was identified in multiple cohorts of individuals diagnosed with ovarian cancer (Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7; Alsop K et al. J. Clin. Oncol. 2012 Jul;30(21):2654-63). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620) and in 1/50726 patients from an unselected population cohort from a single health system who underwent exome sequencing (Manickam K et al. JAMA Netw Open, 2018 09;1:e182140). Of note, this alteration is also designated as 2637T>G in 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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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 individuals with a personal and/or family history of BRCA2-related cancers (Zhang 2011, Alsop 2012, Rebbeck 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 21324516, 25525159, 22711857, 21702907, 29446198, 32885271) -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 19, 2017

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Uncertain	0.24
Eigen_PC	Benign	-0.021
FATHMM_MKL	Benign	0.43	N
MutationTaster	Benign	1.0	A;A
Vest4		0.81
GERP RS		5.6

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: rs80358504; hg19: chr13-32910901; COSMIC: COSV104701427; COSMIC: COSV104701427;