rs397515636

chr13-32338329-C-CTGCT

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.3975_3978dup(p.Ala1327CysfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,433,992 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. T1325T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:27
• Conservation: PhyloP100: 0.784

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 13-32338329-C-CTGCT is Pathogenic according to our data. Variant chr13-32338329-C-CTGCT is described in ClinVar as [Pathogenic]. Clinvar id is 51578.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.3975_3978dup	p.Ala1327CysfsTer4	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.3975_3978dup	p.Ala1327CysfsTer4	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1433992 Hom.: 0 Cov.: 34 AF XY: 0.00000141 AC XY: 1 AN XY: 711248

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: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 03, 2017	This c.3975_3978dup (p.Ala1327Cysfs*4) has previously been reported in at least two patients from two cohorts of 134 and 40 patients respectively [PMID 25366421, 10978364, reported as 4206insTGCT in the latter]. The c.3975_3978dup (p.Ala1327Cysfs*4) variant has been observed in one European (Non Finnish) individual at the heterozygous state in the ExAC database (http://exac.broadinstitute.org/variant/13-32912466-C-CTGCT). This 4 bp duplication is located in exon 11, and leads to the creation of a frameshift and a premature stop codon at amino acid position 1330 of the BRCA2 protein. It is thus classified as pathogenic. This variant is also considered medically actionable [ACMG59, PMID 27854360]. -
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	All of Us Research Program, National Institutes of Health	Jan 22, 2024	This variant inserts 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4206ins4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 20 individuals affected with breast cancer, including 7 male individuals, and 5 individuals affected with ovarian cancer (PMID: 10978364, 16168118, 17148771, 17997147, 18824701, 20104584, 21324516, 25066507, 25330149, 25366421, 28008555, 29161300, 30441849, 33471991; Leiden Open Variation Database DB-ID BRCA2_002096, 33891299, 34949660). This variant has been reported in several hereditary breast and ovarian cancer families (PMID: 21232165, 22923021, 23397983, 29907814, 31409081) and has been identified in 10 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/225036 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	research	Medical Genetics, Medical University Pleven	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Ala1327Cysfs*4 variant was identified in 12 of 3586 proband chromosomes (frequency: 0.003) from European (Slovenian, Czech and Polish) individuals or families with breast and ovarian cancer and male individuals with breast cancer; and was not identified in 80 control chromosomes from healthy individuals (Pohlreich 2005, Stegel 2011, Pritzaff 2016, Novakovic 2012, Ratajska 2015). The variant was also identified in dbSNP (ID: rs764689249) as “NA”, ClinVar (classified pathogenic, reviewed by an expert panel (2019); submitters: ENIGMA, Invitae, Ambry Genetics, GeneDx, and 8 other laboratories), and LOVD 3.0 (1x). The variant was not identified in UMD-LSDB (unavailable) or in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3975_3978dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1327 and leads to a premature stop codon at position 1331. 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. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 02, 2020	- -
Pathogenic, criteria provided, single submitter	research	Institute of Genomics, University of Tartu	-	- -
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	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS4_STR PM2_SUP -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 13, 2020	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in multiple individuals with breast, ovarian, male breast and prostate cancers in the published literature (PMID: 29907814 (2018), 27989354 (2017), 29161300 (2017), 28008555 (2017), 25366421 (2015), 10978364 (2000)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 10, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Plaschke et al., 2000; Lubinski et al., 2004; Pohlreich et al., 2005; Borg et al., 2010; Stegel et al., 2011; Zhang et al., 2011; Novakovic et al., 2012; Karami et al., 2013; Janavicius et al., 2014; Krajc et al., 2014; Ratajska et al., 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4203_4206dupTGCT, 3978insTGCT, and 4206insTGCT; This variant is associated with the following publications: (PMID: 26689913, 31447099, 20104584, 25066507, 29907814, 31159747, 29922827, 30040829, 16168118, 10978364, 21324516, 21232165, 15131399, 26315209, 24312913, 28008555, 22923021, 25366421, 29101607, 27989354, 29161300, 30720243, 29945567, 29625052, 33891299, 35382848, 35409996, 23397983) -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change creates a premature translational stop signal (p.Ala1327Cysfs*4) 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 (rs764689249, gnomAD 0.001%). This premature translational stop signal has been observed in individual(s) with breast cancer and breast and ovarian cancer (PMID: 10978364, 16168118, 20104584, 22923021, 25066507, 25366421). This variant is also known as 4206insTGCT. ClinVar contains an entry for this variant (Variation ID: 51578). 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	Jul 27, 2020	Variant summary: BRCA2 c.3975_3978dupTGCT (p.Ala1327CysfsX4) 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 229858 control chromosomes (gnomAD). c.3975_3978dupTGCT has been reported in the literature in several individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (e.g. Plaschke_2000, Pohlreich_2005, Brozek_2007, Spearman_2008, Borg_2010, Zhang_2011, Novakovic_2012, Krajc_2014, Rebbeck_2018). 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. 11 other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2023	The p.Ala1327CysfsX4 variant in BRCA2 has been reported in >10 individuals with BRCA2-associated cancers, including 7 males (2 prostate; 5 breast cancer; Plaschke 2000 PMID: 10978364, Lu 2015 PMID: 26689913, Ratajska 2015 PMID: 25366421, Alemar 2017 PMID: 29161300, Na 2017 PMID: 27989354, Huang 2018 PMID: 29625052, Palmero 2018 PMID: 29907814, Young 2018 PMID: 29945567, Tsaousis 2019 PMID: 31159747, Strojnik 2021 PMID: 33891299). 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 1327 and leads to a premature termination codon 4 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 autosomal dominant hereditary breast and ovarian cancer (BRCA2). Additionally, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 51578). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Moderate. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This sequence change is a duplication of 4 nucleotides in exon 11 of BRCA2 mRNA (c3975_3978dupTGCT), causing a frameshift after codon 1327 and the creation of a premature translation stop signal 4 amino acid residues later (p.Ala1327Cysfs*4). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular variant has been reported in international bibliography in breast and ovarian cancer patients (PMID: 25366421; PMID: 10978364 The mutation database ClinVar contains an entry for this variant (Variation ID: 51578). This variant is also known as 4206insTGCT in the literature using alternative nomenclature. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 03, 2021	The c.3975_3978dupTGCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of TGCT at nucleotide position 3975, causing a translational frameshift with a predicted alternate stop codon (p.A1327Cfs*4). This mutation has been reported in multiple breast, ovarian, and prostate cancer patients in the literature (e.g. Plaschke J et al. J. Med. Genet. 2000 Sep;37:E17; Pohlreich P et al. Breast Cancer Res. 2005 Jul;7:R728-36; Risch HA et al. J. Natl. Cancer Inst. 2006 Dec;98:1694-706; Ratajska M et al. J. Appl. Genet. 2015 May;56:193-8; Na R et al. Eur. Urol. 2017 05;71(5):740-747; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620), including male breast cancer patients (e.g. Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Strojnik K et al. Breast Cancer Res Treat, 2021 Aug;188:811-820). Of note, this mutation is also designated as 4206ins4 and 4203_4206dupTGCT 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	Nov 29, 2023	This variant inserts 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4206ins4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 20 individuals affected with breast cancer, including 7 male individuals, and 5 individuals affected with ovarian cancer (PMID: 10978364, 16168118, 17148771, 17997147, 18824701, 20104584, 21324516, 25066507, 25330149, 25366421, 28008555, 29161300, 30441849, 33471991; Leiden Open Variation Database DB-ID BRCA2_002096, 33891299, 34949660). This variant has been reported in several hereditary breast and ovarian cancer families (PMID: 21232165, 22923021, 23397983, 29907814, 31409081) and has been identified in 10 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/225036 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. -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Apr 02, 2020

- -

Malignant tumor of prostate Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Sep 28, 2021

- -

Breast carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Oct 05, 2022

_x000D_ Criteria applied: PVS1, PS4, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397515636; hg19: chr13-32912466;