rs80359554

chr13-32340378-A-AG

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.6024dup(p.Gln2009AlafsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,630 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. K2008K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:19
• Conservation: PhyloP100: 0.0650

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 13-32340378-A-AG is Pathogenic according to our data. Variant chr13-32340378-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 38015.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.6024dup	p.Gln2009AlafsTer9	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6024dup	p.Gln2009AlafsTer9	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250690 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135654

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461630 Hom.: 0 Cov.: 46 AF XY: 0.00000138 AC XY: 1 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6

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	Genologica Medica	Jan 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 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 observed in at least 9 individuals affected with breast and ovarian cancer (PMID: 15944772, 22044689, 25236687, 26687385, 28528518, 28947987, 29084914, 30014164, 30103829). This variant has been identified in 1/250690 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)	Sep 27, 2012	- -
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	Breast Cancer Information Core (BIC) (BRCA2)	Jun 20, 2002	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2023	The BRCA2 c.6024dupG; p.Gln2009fs variant (rs80359554) is reported in the literature in multiple individuals with a personal or family history of breast and/or ovarian cancer (Cock-Rada 2018, Labidi-Galy 2018, Rodriguez 2012, Salgado 2005). This variant is found on a single chromosome in the Genome Aggregation Database (1/250690 alleles), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 38015). 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. References: Cock-Rada AM et al. A multi-gene panel study in hereditary breast and ovarian cancer in Colombia. Fam Cancer. 2018 Jan;17(1):23-30. PMID: 28528518. Labidi-Galy SI et al. Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer. Clin Cancer Res. 2018 Jan 15;24(2):326-333. PMID: 29084914. Rodriguez AO et al. BRCA1 and BRCA2 mutations among ovarian cancer patients from Colombia. Gynecol Oncol. 2012 Feb;124(2):236-43. PMID: 22044689. Salgado J et al. Structure-based assessment of BRCA1 and BRCA2 mutations in a small Spanish population. Oncol Rep. 2005 Jul;14(1):85-8. PMID: 15944772 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 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 association with Hereditary Breast and Ovarian Cancer syndrome (Salgado et al., 2005; Rodrguez et al., 2012; Yablonski-Peretz et al., 2016; Torres et al., 2017; Labidi-Galy et al., 2018; Ruiz de Sabando et al., 2019); 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); This variant is associated with the following publications: (PMID: 26687385, 25236687, 34413315, 22044689, 22430266, 15944772, 23966579, 28152038, 28918466, 28680148, 28528518, 29618939, 29084914, 30720243, 30014164, 30322717, 31454914, 31771539, 30787465, 28888541, 29922827, 29884136, 36003761, 32438681) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 03, 2019	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000029 (1/34592 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in affected individuals with breast and/or ovarian cancer (PMIDs: 22044689 (2012), 22430266 (2012), 28528518 (2017), 28985766 (2017), and 30103829 (2018)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 16, 2021	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Gln2009Alafs*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 (rs80359554, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 15944772, 22044689, 25236687, 26687385). This variant is also known as 6252insG. ClinVar contains an entry for this variant (Variation ID: 38015). 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	Dec 17, 2018	Variant summary: BRCA2 c.6024dupG (p.Gln2009AlafsX9) 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. The variant allele was found at a frequency of 4.1e-06 in 245708 control chromosomes (gnomAD). c.6024dupG has been reported in the literature in multiple individuals affected with Breast and/or Ovarian Cancer (Cardoso_2018, Pajares_2018, Villareal-Garza_2015, Chaudhury_2013, Rodriguez_2012, Salgado_2005, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Ten ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2022	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 observed in at least 9 individuals affected with breast and ovarian cancer (PMID: 15944772, 22044689, 25236687, 26687385, 28528518, 28947987, 29084914, 30014164, 30103829). This variant has been identified in 1/250690 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	Ambry Genetics	Jul 06, 2022	The c.6024dupG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of G at nucleotide position 6024, causing a translational frameshift with a predicted alternate stop codon (p.Q2009Afs*9). This alteration has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Salgado J et al. Oncol. Rep. 2005 Jul;14:85-8; Nisman B et al. Cancer Epidemiol. Biomarkers Prev. 2013 Nov;22:2110-5; Villarreal-Garza C et al. Cancer. 2015 Feb;121:372-8; Yablonski-Peretz T et al. Breast Cancer Res. Treat. 2016 Jan;155:133-8; Cock-Rada AM et al. Fam. Cancer. 2017 May; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24(2):326-333). 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. -

BRCA2-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 17, 2023

The BRCA2 c.6024dupG variant is predicted to result in a frameshift and premature protein termination (p.Gln2009Alafs*9). This variant, also referred to as 6252insG, has been reported to be causative for hereditary breast and ovarian cancer (Cock-Rada et al. 2018. PubMed ID: 28528518; Millan Catalan et al. 2019. PubMed ID: 31454914). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38015/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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.Gln2009AlafsX9variant was identified in 1 of 376 proband chromosomes (frequency: 0.003) from individuals or families of Mexicans with Breast cancer (Villarreal-Garza 2014). The variant was identified in dbSNP (ID: rs80359554) “With Pathogenic allele”. The ClinVar database classified the variant as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports), by BIC and by Ambry Genetics. Classification was not provided by Invitae. The variant was identified in BIC database (2X with clinical importance and classified as pathogenic), BRCA Share UMD (5X as causal variant) and ARUP Laboratories 1X as definitely pathogenic. The p.Gln2009AlafsX9 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2009 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

May 18, 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: rs80359554; hg19: chr13-32914515;