rs80359468

chr13-32339181-CTG-C

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.4829_4830del(p.Val1610GlyfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,428 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 0.721

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 13-32339181-CTG-C is Pathogenic according to our data. Variant chr13-32339181-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 51721.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339181-CTG-C is described in Lovd as [Pathogenic]. Variant chr13-32339181-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.4829_4830del	p.Val1610GlyfsTer4	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.4829_4830del	p.Val1610GlyfsTer4	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250066 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135536

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461428 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 09, 2023	This variant deletes 2 nucleotides 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 detected in at least 9 individuals affected with breast or ovarian cancer and in an individual affected with pancreatic cancer (PMID: 12181777, 16455195, 16998791, 22798144, 29506128, 30014164, 30535581). This variant also has been reported as a recurrent mutation in suspected hereditary breast and ovarian cancer families in Brazil (PMID: 29907814, 30535581). This variant has been identified in 2/250066 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	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	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
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. -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	This sequence change creates a premature translational stop signal (p.Val1610Glyfs*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 (rs777265639, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 16455195, 21559243, 21607582, 25476495). ClinVar contains an entry for this variant (Variation ID: 51721). 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	Feb 12, 2020	Variant summary: BRCA2 c.4829_4830delTG (p.Val1610GlyfsX4) 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 250066 control chromosomes (gnomAD). c.4829_4830delTG has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (examples- Liede_2002, Ahn_2007, Alemar_2017, Palmero_2018, 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 27, 2020	ACMG classification criteria: PVS1, PS4, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 07, 2019	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 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 (Liede et al., 2002; Rashid et al., 2006; Ahn et al., 2007; Kim et al., 2012; Rosenthal et al., 2014; Kang et al., 2015; Alemar et al., 2016; Barnes-Kedar et al., 2018; Cipriano et al., 2018; Lowery et al., 2018); 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 5057_5058delTG or 5055_5056delTG; This variant is associated with the following publications: (PMID: 21607582, 12181777, 27425403, 16455195, 21559243, 16998791, 25476495, 22798144, 25863477, 26187060, 26687385, 22340495, 26295337, 29346284, 29506128, 30014164, 30787465, 34645131, 30535581, 29161300, 29922827, 28888541, 30720243, 29907814) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	BRCA2: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 16, 2020	This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 22798144 (2012), 21559243 (2011), 16455195 (2007), 30535581 (2019), 30720243 (2019), 30014164 (2018), 29907814 (2018), 29506128 (2018), 29446198 (2018), 29161300 (2017), and 25476495 (2015)). The frequency of this variant in the general population, 0.0001 (1/10048 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 10, 2022	The c.4829_4830delTG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 4829 to 4830, causing a translational frameshift with a predicted alternate stop codon (p.V1610Gfs*4). This mutation has been reported in multiple breast and/or ovarian cancer families to date (Ahn SH et al. Cancer Lett. 2007 Jan 8;245(1-2):90-5; Faroog A et al. J. Oncol. 2011 Mar;2011:632870; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134(3):1315-26), including multiple cohorts in Brazil (Alemar B et al. Cancer Genet. 2016 Sep;209(9):417-422; Alemar B et al. PLoS ONE. 2017 Nov;12:e0187630; Palmero EI et al. Sci Rep. 2018 Jun;8:9188; Cipriano NM et al. Breast Cancer. 2019 May;26:397-405). In one cohort of individuals undergoing BRCA1/2 testing at a commercial laboratory, approximately 40% of individuals with the c.4829_4830delTG mutation reported partial or full Ashkenazi Jewish ancestry (Rosenthal E et al. Breast Cancer Res. Treat. 2015 Jan;149(1):223-7), and in another study, this alteration was reported in both Ashkenazi and non-Ashkenazi Jewish breast cancer patients (Barnes-Kedar I et al. Breast Cancer Res. Treat. 2018 Nov;172:151-157). This alteration was reported in an individual diagnosed with pancreatic cancer (Lowery MA et al. J. Natl. Cancer Inst. 2018 Oct;110:1067-1074). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this alteration is also designated as 5057delTG 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	Feb 28, 2023	This variant deletes 2 nucleotides 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 detected in at least 9 individuals affected with breast or ovarian cancer and in an individual affected with pancreatic cancer (PMID: 12181777, 16455195, 16998791, 22798144, 29506128, 30014164, 30535581). This variant also has been reported as a recurrent mutation in suspected hereditary breast and ovarian cancer families in Brazil (PMID: 29907814, 30535581). This variant has been identified in 2/250066 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 25, 2023

- -

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: rs80359468; hg19: chr13-32913318;