Variant chr13-32333238-CAAAT-C details in Genebe, Genetics Data Aggregator

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 links:

ACMG classification

Classification made for transcript

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 13-32333238-CAAAT-C is Pathogenic according to our data. Variant chr13-32333238-CAAAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 51187.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32333238-CAAAT-C is described in Lovd as [Pathogenic]. Variant chr13-32333238-CAAAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.1763_1766del	p.Asn588SerfsTer25	frameshift_variant	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.1763_1766del	p.Asn588SerfsTer25	frameshift_variant	10/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460078

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

726336

show subpopulations

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:4

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	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
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	Sharing Clinical Reports Project (SCRP)	Jun 23, 2011	- -

Hereditary breast ovarian cancer syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change creates a premature translational stop signal (p.Asn588Serfs*25) 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 breast and ovarian cancer (PMID: 12942367, 20960228, 25415331). This variant is also known as 1991delATAA, and 1991del4. ClinVar contains an entry for this variant (Variation ID: 51187). For these reasons, this variant has been 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	Oct 04, 2016	The p.Asn588fs variant in BRCA2 has been reported in 7 individuals with BRCA2-as sociated cancers (Laitman 2011, Kanaan 2003, Dobricic 2013, Breast Cancer Inform ation Core (BIC) database) and was absent from large population studies. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 588 and leads to a premature termination codon 25 amino acids downstream. This alteration is then predicted to lead to a truncate d or absent protein. Heterozygous loss of function of the BRCA2 gene is an estab lished disease mechanism in individuals with hereditary breast and ovarian cance r (HBOC). In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300460.2). In s ummary, the p.Asn588fs variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon absence from controls and t he predicted impact to the protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 06, 2022	Variant summary: BRCA2 c.1763_1766delATAA (p.Asn588SerfsX25) results in a 4 nucleotides deletion from exon 10, causing a frameshift which results in a premature termination codon. This is 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 251676 control chromosomes (gnomAD). The variant, c.1763_1766delATAA, has been reported in the literature in many individuals and several families affected with Hereditary Breast And Ovarian Cancer Syndrome (example Laitman_2011, Dobricic_2013, Tea_2014, Torres_2017, Yang_2017, George_2021, Figlioli_2021). These data indicate that the variant is very likely to be associated with disease. Ten submissions have been made to ClinVar after 2014 assessing the variant and all classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 20, 2017	The BRCA2 c.1763_1766delATAA; p.Asn588fs (traditionally known as 1991_1994del4) is published in the medical literature in individuals and families with breast cancer (Kanaan 2003, Torres 2017). The variant is listed in the ClinVar database (Variation ID: 51187), in the dbSNP variant database (rs80359303), but not in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The variant deletes four nucleotides, results in a premature termination codon, and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is classified as pathogenic. References: Kanaan Y et al. Inherited BRCA2 mutations in African Americans with breast and/or ovarian cancer: a study of familial and early onset cases. Hum Genet. 2003 Oct;113(5):452-60. Torres D et al. Prevalence and Penetrance of BRCA1 and BRCA2 Germline Mutations in Colombian Breast Cancer Patients. Sci Rep. 2017 Jul 5;7(1):4713. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 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 and/or family history consistent with pathogenic variants in this gene (Kanaan et al., 2003; Laitman et al., 2011; Donenberg et al., 2016; Torres et al., 2017; Yang et al., 2017); 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 1991del4 and 1991_1994del; This variant is associated with the following publications: (PMID: 20960228, 24156927, 27469594, 12942367, 23635950, 28664506, 28918466, 28680148, 28828701, 31159747, 31921681, 33646313, 30875412, 30787465, 33632156, 30541753, 25415331) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 14, 2018	The BRCA2 c.1763_1766del (p.Asn588Serfs*25) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 36605468 (2023), 35641219 (2022), 33646313 (2021), 28680148 (2017), 28664506 (2017), 27469594 (2016), 25415331 (2014), 24156927 (2014), 23635950 (2013), 20960228 (2011), 12942367 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant deletes 4 nucleotides in exon 10 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 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	Feb 14, 2022	The c.1763_1766delATAA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1763 to 1766, causing a translational frameshift with a predicted alternate stop codon (p.N588Sfs*25). This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) families (Kanaan Y et al. Hum Genet. 2003 Oct;113(5):452-60; Dobrii J et al. J Hum Genet. 2013 Aug;58(8):501-7; Laitman Y et al. Breast Cancer Res Treat. 2011 Jun;127(2):489-95; Tea M et al Maturitas. 2014 Jan;77(1):68-72; Bolognesi C et al. PLoS One, 2014 Nov;9:e112354; Donenberg T et al. Breast Cancer Res Treat, 2016 08;159:131-8; Torres D et al. Sci Rep. 2017 Jul;7:4713; Yang XR et al. Breast Cancer Res. Treat. 2017 Oct;165:687-697; Ow SGW et al. PLoS One, 2019 Mar;14:e0213746; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 1991delATAA 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. -

Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneKor MSA

Jan 01, 2020

This variant is a 4 bp deletion at amino acid residue 588 of the BRCA2 gene. It results in a frame-shift creating an unrecognizable protein after amino acid 588 and a new stop codon 25 amino acid residues later, thus resulting in a truncated protein. -

Computational scores

Source: dbNSFP v4.3

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Calibrated prediction

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Splicing

Name

Calibrated prediction

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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

Below is the list of publications found by LitVar. It may be empty.

chr13-32333238-CAAAT-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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