rs606231401

Positions:

• chr13-32338633-A-AT
• chr13-32338633-AT-A

Variant summary

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

The NM_000059.4(BRCA2):​c.4284dup​(p.Gln1429SerfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,446,458 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T1426T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:31
• Conservation: PhyloP100: 0.499

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 13-32338633-A-AT is Pathogenic according to our data. Variant chr13-32338633-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 37892.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.4284dup	p.Gln1429SerfsTer9	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.4284dup	p.Gln1429SerfsTer9	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244426 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132610

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: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1446458 Hom.: 0 Cov.: 35 AF XY: 0.00000977 AC XY: 7 AN XY: 716644

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000239

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000127

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:31

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:12

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	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 30, 2018	This c.4284_4285insT (p.Gln1429Serfs*9) variant in the BRCA2 gene has been reported in multiple breast cancer and ovarian cancer patient [PMID: 21120943, 22085629, 24728189] while only observed once in general population according to gnomad 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 evidences, this c.4284_4285insT (p.Gln1429Serfs*9) variant in the BRCA2 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Dec 28, 2020	The heterozygous c.4284dup (p.Gln1429SerfsTer9) variant identified in exon 11 (of 27) of the BRCA2 gene alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported in multiple unrelated individuals affected with BRCA2-associated disorders [PMID: 11179017;PMID: 26360800;PMID: 28657667;PMID: 29753700]. This variant has also been reported as pathogenic in the ClinVar database by multiple independent laboratories (Variation ID: 37892). The variant is absent from the gnomAD(v3) database indicating it is an extremely rare allele in the populations represented in that database. Based on the available evidence, the heterozygous c.4284dup (p.Gln1429SerfsTer9) variant identified in the BRCA2 gene is reported as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals affected with breast and ovarian cancer (PMID: 11179017, 21324516, 22085629, 24728189, 27741520, 29084914, 30128899, 33471991; Leiden Open Variation Database DB-ID BRCA2_001668) and in suspected hereditary breast and ovarian cancer families (PMID: 21120943, 24156927, 29483665). This variant also has been reported in an individual affected with prostate cancer with multiple primary malignancies and another individual affected with medulloblastoma (PMID: 28657667, 29753700). This variant has been identified in 1/244426 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, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 30, 2012	- -
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 Genetics Bochum, Ruhr University Bochum	Mar 08, 2022	ACMG criteria used to clasify this variant: PVS1, PS4, PM1, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 06, 2023	BRCA2 (p.Gln1429fs): This insertion of one nucleotide in BRCA2 is denoted c.4284insT at the cDNA level and p.Gln1429SerfsX9 (Q1429SfsX9) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ATTTTT[insT]CAGA. The duplication causes a frameshift, which changes a Glutamine to a Serine at codon 1429 and creates a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.4284insT, previously reported as 4510dupT or 4512dupT using alternate nomenclature. The BRCA2 c.4284insT; p.Gln1429fs variant is reported in the literature in multiple individuals affected with breast or ovarian cancer or that met criteria for hereditary breast and/or ovarian cancer (HBOC) syndrome (Fernandes 2016, Koumpis 2011, Palmero 2018, Risch 2001, Zhang 2011, Zuradelli 2010). This variant is present on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37892). This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Dec 29, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 11, 2021	Variant summary: BRCA2 c.4284dupT (p.Gln1429SerfsX9) 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 4e-06 in 247482 control chromosomes (gnomAD). c.4284dupT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Risch_2001, Caux-Moncoutier_2011, Song_2014, Tea_2014, Fernandes_2016). These data indicate that the variant is very likely to be associated with disease. Thirteen clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This sequence change inserts one nucleotide in exon 11 of the BRCA2 mRNA (c.4284dupT), causing a frameshift after codon 1429 and the creation of a premature translation stop signal 9 amino acid residues later p.(Gln1429Serfs*9). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This variant is also known as 4510insT and 4512insT in the international literature and has been reported in individuals affected with breast and ovarian cancer (PMID: 11179017, 20373018, 22085629, 24156927, 24728189). The mutation database ClinVar contains entries for this variant (Variation ID: 37892). -
Pathogenic, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 15, 2021	The p.Gln1429SerfsX9 variant in BRCA2 has been reported in >10 individuals with BRCA2-associated cancers (Risch 2001 PMID:11179017, Zuradelli 2010 PMID:20373018, Zhang 2011 PMID:21324516, Koumpis 2011 PMID:22085629, Caux-Moncoutier 2011 PMID:21120943, Song 2014 PMID:24728189, Pilie 2017 PMID:28657667, Nielsen 2016 PMID:26360800, Palmero 2018 PMID:29907814, Waszak 2018 PMID:29753700, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1429 and leads to a premature termination codon 9 amino acids downstream. This alteration is then 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). Additionally, this variant was classified as pathogenic on Sept 13, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 37892). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria Applied: PS4_Moderate, PM2_Supporting, PVS1. -
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	Dec 27, 2023	This sequence change creates a premature translational stop signal (p.Gln1429Serfs*9) 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 (rs80359439, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 11179017, 20373018, 22085629, 24156927, 24728189). This variant is also known as 4510insT and 4512insT. ClinVar contains an entry for this variant (Variation ID: 37892). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	BRCA2: PVS1, PS4:Moderate, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 21, 2019	PVS1, PS4_Mod, PM1, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 14, 2020	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, the variant has been reported in individuals affected with breast/ovarian and prostate cancer in the published literature (PMID: 28657667 (2017), 27741520 (2016), 21120943 (2011), 22085629 (2011), 11179017 (2001)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2023	Frameshift 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 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 4512dupT; This variant is associated with the following publications: (PMID: 21120943, 27836010, 22085629, 24728189, 22762150, 24156927, 24670361, 20373018, 11179017, 27741520, 29061375, 28657667, 29907814, 26360800, 29753700, 21324516, 21702907, 23942203, 30128899, 29641532, 29084914, 30720243, 31368036, 31336956, 29483665, 31447099, 32846166, 32295079, 32438681, 32719484, 32853339, 32782288, 28888541, 36988593, 36329109, 37179432, 36136896, 35205366, 35463374, 35216584) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 18, 2022	The c.4284dupT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 4284, causing a translational frameshift with a predicted alternate stop codon (p.Q1429Sfs*9). This mutation has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Koumpis C et al. Hered Cancer Clin Pract. 2011;9:10; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Labidi-Galy SI et al. Clin. Cancer Res. 2018 01;24:326-333; Marchetti C et al. Ann. Surg. Oncol. 2018 Nov;25:3701-3708; Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620), an individual with prostate cancer (Pilie PG et al. Cancer. 2017 Oct;123(20):3925-3932), and one individual with medulloblastoma diagnosed in infancy (Waszak SM et al. Lancet Oncol. 2018 06;19:785-798). Of note, this alteration is also designated as 4512insT and 4510insT 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	Jan 03, 2023	This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals affected with breast and ovarian cancer (PMID: 11179017, 21324516, 22085629, 24728189, 27741520, 29084914, 30128899, 33471991; Leiden Open Variation Database DB-ID BRCA2_001668) and in suspected hereditary breast and ovarian cancer families (PMID: 21120943, 24156927, 29483665). This variant also has been reported in an individual affected with prostate cancer with multiple primary malignancies and another individual affected with medulloblastoma (PMID: 28657667, 29753700). This variant has been identified in 1/244426 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;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 19, 2022

- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

BRCA2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 27, 2023

The BRCA2 c.4284dupT variant is predicted to result in a frameshift and premature protein termination (p.Gln1429Serfs*9). This variant (also known as 4512dupT and 4510insT) has been frequently reported in the literature as pathogenic in individuals with a personal and/or family history of breast and ovarian cancer (see, for example, Table 1, Risch et al. 2001. PubMed ID: 11179017; Zuradelli et al. 2010. PubMed ID: 20373018; Table 1, Fernandes et al. 2016. PubMed ID: 27741520). This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32912770-A-AT). In ClinVar, this variant has been reviewed by an expert panel and is interpreted as pathogenic by numerous laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/37892/). Truncating variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

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.Gln1429SerfsX9 variant was identified in 3 of 4408 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancers (Caux-Moncoutier 2011, Risch 2001, Terabeax 2014). The variant was identified by our laboratory in 1 individual who was unaffected at the time of testing. The variant was also identified in dbSNP (ID: rs80359439 “With pathogenic allele”. The p.Gln1429SerfsX9variant was identified in the Clinvar database and classified as pathogenic by Invitae, Ambry Genetics, GeneDx, BIC and Sharing clinical Reports project. Counsy classified the variant as likely pathogenic. In the BRCA Share UMD database, the variant was identified 14x and classified as causal. The variant was identified with a co-occurring pathogenic BRCA1 variant (c.5266dup (p.Gln1756ProfsX74). The BIC database identified the variant 4X with clinical importance and classified as pathogenic. The ARUP laboratory identified the variant 1x and classified it as pathogenic. The p.Gln1429SerfsX9 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1429 and leads to a premature stop codon 9 codons downstream. This alteration is then predicted to result in 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 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs80359439; hg19: chr13-32912770;