rs80358533

chr13-32337185-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):c.2830A>T(p.Lys944Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,668 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:30
• Conservation: PhyloP100: -0.0630

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32337185-A-T is Pathogenic according to our data. Variant chr13-32337185-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 51355.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337185-A-T is described in Lovd as [Pathogenic]. Variant chr13-32337185-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.2830A>T	p.Lys944Ter	stop_gained	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.2830A>T	p.Lys944Ter	stop_gained	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250612 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135612

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: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461430 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727002

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	New York Genome Center	Mar 10, 2020	The c.2830A>T (p.Lys944Ter) variant identified in the BRCA2 gene of this individual leads to the premature termination of the protein at amino acid 944/3419 (coding exon 11/27). This variant is found with low frequency in gnomAD (3 heterozygotes, 0 homozygotes, allele frequency: 1.06e-5) suggesting it is not a common benign variant in the populations represented in these databases. This variant is reported as Pathogenic in ClinVar (VarID:51355) after review by the Expert Panel and has been reported in many affected individuals in the literature [PMID: 24737347; PMID: 23683081; PMID: 20104584; PMID: 28346442]. It is reported here as Pathogenic. -
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)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 27, 2006	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 11, 2015	- -
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	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 06, 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 individuals with a personal and/or family history of breast, ovarian, or pancreatic cancer (PMID: 18465347, 18284688, 19574032, 20104584, 22535016, 23096105, 23683081, 29446198, 30322717, 32885271, 34072659. 34309133). This variant has been identified in 3/282020 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. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 26, 2019	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in a number of individuals with breast and ovarian cancers (PMID: 27767231 (2017), 26681312 (2015), 23940062 (2013), 23683081 (2013), 20104584 (2010), 16760289 (2006), 9150154 (1997)) and in one case of pancreatic cancer (PMID: 29506128 (2018)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
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; 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; This variant is associated with the following publications: (PMID: 25525159, 26659639, 20104584, 23683081, 26064523, 25428789, 9150154, 16760289, 23940062, 22535016, 11430722, 20608899, 10359546, 16847550, 14732925, 24737347, 9892109, 18465347, 11710835, 27767231, 27836010, 28127413, 26681312, 29339979, 28993434, 29506128, 29446198, 30720243, 30702160, 30322717, 31589614, 32885271, 33087929, 33287145) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 30, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Lys944X variant in BRCA2 has been reported in at least 11 individuals with BRCA2-related cancers; however two of these individuals harbored pathogenic variants in BRCA1 as well (Hakansson 1997, Heidemann 2012, Vietri 2013, Susswein 2016, Weren 2017, Lowery 2018, Wen 2018, BIC database). In addition, this variant was reported in one proband with Fanconi anemia who was compound heterozygous for this variant and a second variant in BRCA2 (Bodd 2010). The p.Lys944X variant has also been identified in 0.004% (1/24868) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, 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 is predicted to lead to a premature termination codon at position 944. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. Additionally, this variant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 51355). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	This sequence change creates a premature translational stop signal (p.Lys944*) 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 (rs80358533, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150154, 20104584, 23683081, 26681312, 27836010). This variant is also known as 3058A>T. ClinVar contains an entry for this variant (Variation ID: 51355). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 30, 2021	Variant summary: BRCA2 c.2830A>T (p.Lys944X) 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 250612 control chromosomes. c.2830A>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple 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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	research	Research Institute, Aichi Cancer Center	Feb 01, 2022	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 20, 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 and/or family history of breast, ovarian, or pancreatic cancer (PMID: 18465347, 18284688, 19574032, 20104584, 22535016, 23096105, 23683081, 29446198, 30322717, 32885271, 34072659. 34309133). This variant has been identified in 3/282020 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jun 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 01, 2021	The p.K944* pathogenic mutation (also known as c.2830A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 2830. This changes the amino acid from a lysine to a stop codon within coding exon 10. This mutation has been detected in multiple breast and ovarian cancer families to date (Mote PA et al. Genes Chromosomes Cancer, 2004 Mar;39:236-48; Capalbo C et al. Ann Oncol, 2006 Jun;17 Suppl 7:vii34-40; Thomassen M et al. Acta Oncol, 2008;47:772-7; Bodd TL et al. Acta Paediatr., 2010 Nov;99:1741-3; Heidemann S et al. Breast Cancer Res Treat, 2012 Aug;134:1229-39; Vietri MT et al. Clin. Chem. Lab. Med., 2013 Dec;51:2319-24; Lucas AL et al. Cancer, 2014 Jul;120:1960-7; Rebbeck TR et al. Breast Cancer Res, 2016 11;18:112; Susswein LR et al. Genet Med, 2016 08;18:823-32; Weren RD et al. Hum. Mutat., 2017 02;38:226-235; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Wen WX et al. J Med Genet, 2018 02;55:97-103; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Chen B et al. Aging (Albany NY), 2020 02;12:3140-3155; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In one study, this variant was reported in 2/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in patients with pancreatic cancer (Lowery MA et al. J Natl Cancer Inst, 2018 10;110:1067-1074; Sorscher S et al. Oncologist, 2021 Jul). Of note, this alteration is also designated as 3058A>T in the 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. -

Fanconi anemia complementation group D1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Feb 05, 2020

- -

Neoplasm of ovary Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

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.Lys944X variant was identified in 8 of 25752 proband chromosomes (frequency: 0.0003) from individuals or families with breast and ovarian cancer (Blay 2013, Borg 2010, Capalbo 2006, Hakansson 1997, Heramb 2018, Susswein 2015). The variant was also identified in the following databases: dbSNP (ID: rs80358533) as "With Pathogenic allele", ClinVar (12x pathogenic), Clinvitae (5x pathogenic), GeneInsight-COGR (2x pathogenic), Cosmic (1x, confirmed somatic, in carcinoma of the biliary tract), LOVD 3.0 (11x), UMD-LSDB (8x causal), BIC Database (6x pathogenic), and ARUP Laboratories (pathogenic). The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 3 of 276604 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 23994 chromosomes (freq: 0.00004), European in 1 of 126388 chromosomes (freq: 0.000008), and South Asian in 1 of 30678 chromosomes (freq: 0.00003). The variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The c.2830A>T variant leads to a premature stop codon at position 944 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	26
Dann	Uncertain	0.98
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.15	N
MutationTaster	Benign	1.0	A;A
Vest4		0.81
GERP RS		-1.2

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: rs80358533; hg19: chr13-32911322; COSMIC: COSV66450359; COSMIC: COSV66450359;