13-32340212-G-T

Position:

• chr13-32340212-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.5857G>T​(p.Glu1953*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,582 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:37
• Conservation: PhyloP100: 0.236

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 13-32340212-G-T is Pathogenic according to our data. Variant chr13-32340212-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 51952.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340212-G-T is described in Lovd as [Pathogenic]. Variant chr13-32340212-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5857G>T	p.Glu1953*	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.5857G>T	p.Glu1953*	stop_gained	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5488G>T	p.Glu1830*	stop_gained	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5857G>T		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250950 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461582 Hom.: 0 Cov.: 46 AF XY: 0.00000138 AC XY: 1 AN XY: 727080

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:37

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:11

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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 15, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Mar 23, 2021	Incidental finding in clinical exome sequencing. PVS1, PS1 -
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	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 09, 2023	The c.5857G>T (p.Glu1953*) variant in the BRCA2 gene is located on the exon 11 and is predicted to introduce a premature translation termination codon (p.Glu1953*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast/ovarian/pancreatic cancer and it is one of the frequently reported variants in French Canadian population (PMID: 34298626, 28503720, 35949895, 35714671, 26425718, 32772980). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 51952) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (2/250950). Therefore, the c.5857G>T (p.Glu1953*) variant of BRCA2 has been classified as pathogenic. -
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	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1; PM5_PTC_Strong -

not provided Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 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; French Canadian pathogenic founder variant observed in multiple families with breast, ovarian, and prostate cancer (Serova-Sinilnikova 1997, Frank 1998, Tonin 1998, Oros 2004, Zhang 2011, Taherian 2013, Belanger 2015); Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 6085G>T; This variant is associated with the following publications: (PMID: 25525159, 21324516, 25884701, 7478555, 9667259, 23621881, 23199084, 32772980, 32300229, 9150172, 23318356, 26425718, 9792861, 19863560, 15382066, 17386038, 20694749, 28715532, 28503720, 16905680, 27741520, 26786923, 29907814, 29446198, 30274973, 30720243, 32885271, 32338768, 30787465, 31360904) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2022	The BRCA2 c.5857G>T; p.Glu1953Ter variant (rs80358814), also reported as 6085G>T, has been described in multiple individuals affected with hereditary breast and ovarian cancer (HBOC), including prostate and male breast cancers (Pritzlaff 2017, Serova-Sinilnikova 1997, Taherian 2013, Tonin 1998, van der Hout 2006) and is a common cause of HBOC in the French Canadian population (Ghadirian 2014, Oros 2004). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 51952) and is observed on only 2 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. REFERENCES Ghadirian P et al. Screening for BRCA1 and BRCA2 mutations among French-Canadian breast cancer cases attending an outpatient clinic in Montreal. Clin Genet. 2014 Jan;85(1):31-5. PMID: 23621881. Oros K et al. Significant proportion of breast and/or ovarian cancer families of French Canadian descent harbor 1 of 5 BRCA1 and BRCA2 mutations. Int J Cancer. 2004 Nov 10;112(3):411-9. PMID: 15382066. Pritzlaff M et al. Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results. Breast Cancer Res Treat. 2017 Feb;161(3):575-586. PMID: 28008555. Serova-Sinilnikova O et al. BRCA2 mutations in hereditary breast and ovarian cancer in France. Am J Hum Genet. 1997 May;60(5):1236-9. PMID: 9150172. Taherian N et al. Familial prostate cancer: the damage done and lessons learnt. Nat Rev Urol. 2013 Feb;10(2):116-22. PMID: 23318356. Tonin P et al. Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families. Am J Hum Genet. 1998 Nov;63(5):1341-51. PMID: 9792861. van der Hout A et al. A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. Hum Mutat. 2006 Jul;27(7):654-66. PMID: 16683254 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 07, 2022	This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000008 (2/250950 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, this variant has been described in individuals/families with breast/ovarian cancer (PMIDs: 33471991 (2021), 32885271 (2021), 32772980 (2020), 28503720 (2017), 28008555 (2017), 27741520 (2016), 21324516 (2011), 20694749 (2010), 17148771 (2006), 9667259 (1998), 9792861 (1998), and 8673090 (1996)) and described as a common French-Canadian founder variant (PMIDs: 25884701 (2015), 23621881 (2014), 15382066 (2004), 11307153 (2001), and 9792861 (1998)). This variant has also been reported in individuals with prostate cancer (PMIDs: 23318356 (2013) and 32338768 (2020)) and pancreatic cancer (PMID: 30274973 (2018)). Based on the available information, this variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Glu1953*) 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 present in population databases (rs80358814, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 9150172, 9792861, 15382066, 16683254, 23318356, 23621881, 28008555). It is commonly reported in individuals of French Canadian ancestry (PMID: 9150172, 9792861, 15382066, 16683254, 23318356, 23621881, 28008555). This variant is also known as 6085G>T. ClinVar contains an entry for this variant (Variation ID: 51952). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 30, 2020	The p.Glu1953X variant in BRCA2 has been reported in numerous individuals with BRCA2-associated cancers and segregated with disease in 4 affected individuals from one family (Phelan 1996 PMID: 8673090; Serova-Sinilnikova 1997 PMID: 9150172; Ghadirian 2009 PMID: 19863560; Taherian 2013 PMID: 233108356; Ghadirian 2014 PMID: 23621881; Fernandes 2016 PMID: 27741520; Bannon 2018 PMID: 30274973; Pritzlaff 2017 PMID: 28008555; Breast Cancer Information Core (BIC) database; https://research.nhgri.nih.gov/bic/)). It has also been identified in 0.002% (2/113514) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This nonsense variant leads to a premature termination codon at position 1953, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. Additionally, this variant was classified as pathogenic on Sept. 13, 2016, by the ClinGen-approved ENIGMA expert panel (SCV000300944.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PM2_Supporting, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2020	Variant summary: BRCA2 c.5857G>T (p.Glu1953X) 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 allele was found at a frequency of 8e-06 in 250950 control chromosomes. c.5857G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Frank_1998, Ghadirian_2014, Oros_2004, Serova-Sinilnikova_1997). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fifteen clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters 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	- -

Breast and/or ovarian cancer Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Oct 28, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 12, 2023	- -

BRCA2-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The BRCA2 c.5857G>T (p.Glu1953Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Glu1953Ter variant has been reported in at least seven studies in individuals with breast, ovarian or prostate cancer in which it is found in a heterozygous state in at least 44 patients. The variant is a common cause of breast and ovarian cancer in the French Canadian population (Serova-Sinilnikova et al. 1997; Tonin et al. 1998; Oros et al. 2004; van der Hout et al. 2006; Cavallone et al. 2010; Taherian et al. 2014; Ghadirian et al. 2014). Control data are unavailable from these studies for this variant, which is reported at a frequency of 0.00001 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. Although the p.Glu1953Ter variant has not been reported in any cases of Fanconi anemia, it is generally accepted that pathogenic variants in the BRCA2 gene also confer carrier status for Fanconi anemia. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Glu1953Ter variant is classified as pathogenic for BRCA2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 30, 2024	The BRCA2 c.5857G>T variant is predicted to result in premature protein termination (p.Glu1953*). In the literature, this variant is also referred to as c.6085G>T. This variant has been reported in multiple individuals with hereditary breast and ovarian cancer (HBOC) and prostate cancer (Serova-Sinilnikova et al. 1997. PubMed ID: 9150172; Tonin et al. 1998. PubMed ID: 9792861; van der Hout et al. 2006. PubMed ID: 16683254; Taherian et al. 2013. PubMed ID: 23318356; Pritzlaff et al. 2017. PubMed ID: 28008555). Of note, the c.5857G>T (p.Glu1953*) variant is a common cause of HBOC in the French Canadian population (Tonin et al. 1998. PubMed ID: 9792861; Tonin et al. 2001. PubMed ID: 11307153; Oros et al. 2004. PubMed ID: 15382066). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51952/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Mar 23, 2021	Incidental finding in clinical exome sequencing. PVS1, PS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 27, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 08, 2024	The p.E1953* pathogenic mutation (also known as c.5857G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 5857. This changes the amino acid from a glutamic acid to a stop codon within coding exon 10. This pathogenic mutation is considered a founder mutation in the French Canadian population and has been detected in numerous hereditary breast and/or ovarian cancer families to date (Phelan CM et al. Nat. Genet. 1996 May;13(1):120-2; Serova-Sinilnikova OM et al. Am. J. Hum. Genet. 1997 May;60(5):1236-9; Frank TS et al. J. Clin. Oncol. 1998 Jul;16(7):2417-25; Oros KK et al. Int. J. Cancer. 2004 Nov;112(3):411-9; Cavallone L et al. Fam. Cancer. 2010 Dec;9(4):507-17; Taherian N et al. Nat Rev Urol. 2013 Feb;10(2):116-22; Ghadirian P et al. Clin. Genet. 2014 Jan;85(1):31-5; Fernandes GC et al. Oncotarget. 2016 Dec;7(49):80465-80481). Of note, this alteration is also designated as 6085G>T 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 30, 2023	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 individuals with a personal or family history of prostate, breast, and/or ovarian cancer (PMID: 9150172, 9792861, 15382066, 16683254, 19863560, 23318356, 23621881, 28008555, 29446198, 33471991). This variant has been identified in 2/250950 chromosomes 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. -

Medulloblastoma;C0040588:Tracheoesophageal fistula;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

Medulloblastoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Mar 23, 2021

Incidental finding in clinical exome sequencing. PVS1, PS1 -

Malignant tumor of prostate Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Mar 23, 2021

Incidental finding in clinical exome sequencing. PVS1, PS1 -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Glu1953X variant was identified in 28 of 10010 proband chromosomes (frequency: 0.003) from individuals or families with breast, ovarian, and prostate cancer, and it was present in 1 of 3994 control chromosomes (frequency: 0.0002) from healthy individuals (Belanger 2015, Cavallone 2010, Ghadirian 2009, Janavicius 2010, Lubinski 2004, Serova-Sinilnikova 1997, Taherian 2013, Thompson 2016, Tonin 2001, Zhang 2011). The variant was also identified in dbSNP (ID: rs80358814) as “With Pathogenic allele”, ARUP Laboratories BRCA Mutations Database (classified as definitely pathogenic), the ClinVar database (classified as pathogenic 16x including by ENIGMA, Invitae, Ambry Genetics, and GeneDx), the BIC database (32x with clinical importance), UMD (6x with a “causal” classification). The variant was also identified in control databases including the Genome Aggregation Consortium database in 3 of 246032 chromosomes (freq. 0.00001) in the following populations: European in 3 of 111544 chromosomes (freq. 0.00003). The variant was also identified by our laboratory in 5 individuals with breast and pancreatic cancer. The variant described in the literature as a French-Canadian founder mutation (Belanger 2015, Cavallone 2010, Ghadirian 2009, Janavicius 2010, Lubinski 2004, Tonin 2001). The variant has also been described in a Brazilian population (Fernandes 2016). In addition, one case study suggests the variant lead to early-onset and aggressive prostate cancer (Taherian 2013). The p.Glu1953X variant leads to a premature stop codon at position 1953, 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. -

Wilms tumor 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Mar 23, 2021

Incidental finding in clinical exome sequencing. PVS1, PS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	-0.044
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.16	N
Vest4		0.89
GERP RS		1.9

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: rs80358814; hg19: chr13-32914349;