rs80359306

Positions:

• chr13-32333283-GA-G
• chr13-32333283-GA-GAA

Variant summary

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

The NM_000059.4(BRCA2):​c.1813del​(p.Ile605TyrfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000937 in 1,601,250 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:29 U:1 O:1
• Conservation: PhyloP100: 0.512

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 13-32333283-GA-G is Pathogenic according to our data. Variant chr13-32333283-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 37763.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32333283-GA-G is described in Lovd as [Pathogenic]. Variant chr13-32333283-GA-G is described in Lovd as [Pathogenic]. Variant chr13-32333283-GA-G is described in Lovd as [Pathogenic]. Variant chr13-32333283-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1813del	p.Ile605TyrfsTer9	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	c.1813del	p.Ile605TyrfsTer9	frameshift_variant	10/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151588 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000345 AC: 8 AN: 232106 Hom.: 0 AF XY: 0.0000397 AC XY: 5 AN XY: 126070

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000975

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000966 AC: 14 AN: 1449662 Hom.: 0 Cov.: 35 AF XY: 0.00000832 AC XY: 6 AN XY: 720948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000718

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000360

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000632

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151588 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73980

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:29 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8 Uncertain:1

Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 06, 2023	The BRCA2 c.1813delA (p.Ile605Tyrfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not found in the large, broad control population, ExAC. Multiple publications have cited the variant in affected individuals, along with multiple reputable databases/clinical diagnostic laboratories have cited the variant as "pathogenic." ClinVar has 14 entries for this variant, all of which described it as pathogenic. Therefore, the variant of interest has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 22, 2012	- -
Pathogenic, no assertion criteria provided	case-control	Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	May 24, 2021	- -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS4_STR -
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	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 27, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1; PM5_PTC_Strong -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Nov 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	BRCA2: PVS1, PM2, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 09, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 25, 2022	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, 0.00011 (3/26880 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals and families with breast and/or ovarian cancer (PMIDs: 29348823 (2017), 27062684 (2016), 24549055 (2014), 23035815 (2012), 20104584 (2010), 19016756 (2008), 17851763 (2008), 11389159 (2001)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 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 (Bergthorsson et al., 2001; Spearman et al., 2008; Sugano et al., 2008; Hirasawa et al., 2017; Lang et al., 2017; Dudley 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 2041delA; This variant is associated with the following publications: (PMID: 12203997, 35448200, 32438681, 23035815, 11389159, 18824701, 19016756, 27062684, 29348823, 29360161, 26026974, 21318380, 20104584, 17851763, 15131399, 12442265, 11802209, 30287823, 30702160, 28294317, 26187060, 26848529, 31454914, 29176636, 33573335, 32365798, 32856869, 33572923, 33646313, 32853339, 31825140, 32338768, 30787465, 36243179, 35264596, 32980694, 32868316, 28888541, 33804961, 33758026, 36988593) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Ile605Tyrfs*9 variant was identified in 53 of 76928 proband chromosomes (frequency: 0.0007) from individuals or families with breast or ovarian cancer and was present in 2 of 22482 control chromosomes (frequency: 0.00009) from healthy individuals (Bergthorsson 2001, Li 2008, Sugano 2008, Castera 2014, de Juan 2015, Momozawa 2018, Rebbeck 2018). The variant was also identified in dbSNP (ID: rs80359307) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics and eleven other submitters), LOVD 3.0 (18X as pathogenic), and UMD-LSDB (5x as causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1813del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 605 and leads to a premature stop codon at position 613. 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 breast or 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, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 23, 2020	- -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 08, 2018	The p.Ile605fs variant in BRCA2 has been reported in >25 individuals with BRCA2-associated cancers (Bergthorsson 2001, Spearman 2008, Sugano 2008, Borg 2010, Blay 2013, Castera 2014, Azzollini 2016, Hirasawa 2017, Breast Cancer Information Core (BIC) database), and segregated with disease in at least 3 individuals. It was also absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 605 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 individuals with HBOC. In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon predicted impact to the protein. ACMG/AMP Criteria Applied: PVS1, PS4, PM2. -
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	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change creates a premature translational stop signal (p.Ile605Tyrfs*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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer and prostate cancer (PMID: 11389159, 18824701, 19016756, 20104584, 23035815, 23704984, 24549055). This variant is also known as 2041delA. ClinVar contains an entry for this variant (Variation ID: 37763). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	Oct 13, 2016	Variant summary: The BRCA2 c.1813delA (p.Ile605Tyrfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g. c.1813dupA (p.Ile605fs), c.1832C>A (p.Ser611X), and c.1842dupT (p.Asn615X)). The variant of interest was not found in the large, broad control population, ExAC (115908 chrs tested). Multiple publications have cited the variant in affected individuals, along with multiple reputable databases/clinical diagnostic laboratories have cited the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jul 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 08, 2023	This variant deletes 1 nucleotide 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 been reported in at least 30 individuals affected with breast and/or ovarian cancer (PMID: 11389159, 12203997, 16912212, 17851763, 18824701, 20104584, 23704984, 26026974, 27153395, 28294317, 29348823, 30287823, 32438681) that includes in a breast cancer case-control study where this variant was detected in 18/7051 female cases and 1/11241 unaffected controls (OR=28.7, 95% CI 4.5 to 1190.4) (PMID: 30287823). This variant also has been detected in at least five individuals affected with prostate cancer (PMID: 23035815, 31214711). This variant has been identified in 8/232106 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	Sep 08, 2021	The c.1813delA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1813, causing a translational frameshift with a predicted alternate stop codon (p.I605Yfs*9). This mutation has been identified in multiple individuals with familial and/or early onset breast cancer (Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Patmasiriwat P et al. Hum. Mutat. 2002 Sep;20:230; Sugano K et al. Cancer Sci. 2008 Oct;99:1967-76; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Li WF et al. Breast Cancer Res. Treat. 2008 Jul;110:99-109; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71; Hirasawa A et al. Oncotarget. 2017 Dec;8:112258-112267). Additionally, this mutation was observed in multiple men diagnosed with prostate cancer (Willems-Jones A et al. BJU Int. 2012 Dec;110(11 Pt C):E1181-6; de Juan I et al. Fam. Cancer. 2015 Dec;14(4):505-13; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149). Of note, this alteration is also designated as 2041delA 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:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 25, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2024	- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 04-02-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

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: rs80359306; hg19: chr13-32907420;