rs80359283

Variant names:

• chr13-32332866-CAG-C
• rs80359283
• NM_000059.4:c.1389_1390delAG

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.1389_1390delAG​(p.Val464GlyfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,534 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: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:19
• Conservation: PhyloP100: 0.281

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 13-32332866-CAG-C is Pathogenic according to our data. Variant chr13-32332866-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 51113.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332866-CAG-C is described in Lovd as [Pathogenic]. Variant chr13-32332866-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1389_1390delAG	p.Val464GlyfsTer3	frameshift_variant	Exon 10 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1389_1390delAG	p.Val464GlyfsTer3	frameshift_variant	Exon 10 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.1020_1021delAG	p.Val341GlyfsTer3	frameshift_variant	Exon 10 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.1389_1390delAG		non_coding_transcript_exon_variant	Exon 9 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459534 Hom.: 0 AF XY: 0.00000276 AC XY: 2 AN XY: 725894

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

Submissions by phenotype

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

Apr 22, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 26, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 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 been reported in at least 5 individuals affected with breast or ovarian cancer, including 2 male individuals (PMID: 21190077, 22711857, 24549055, 30287823, 34490083) and has been identified in 27 families among the CIMBA participants (PMID: 29446198). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 4/60466 cases and 2/53461 controls (OR=1.768 (95%CI 0.324 to 9.655); p-value=0.691) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001848). 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. -

not provided Pathogenic:4

Jun 14, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This deletion of 2 nucleotides in BRCA2 is denoted c.1389_1390delAG at the cDNA level and p.Val464GlyfsX3 (V464GfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAAC[delAG]TGGT. The deletion causes a frameshift, which changes a Valine to a Glycine at codon 464, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.1389_1390delAG, also published as BRCA2 1617_1618delAG or BRCA2 1617delAG using alternate nomenclature, has been reported in association with Hereditary Breast and Ovarian cancer (Goelen 1999, Claes 2004, Machackova 2008). We consider this variant to be pathogenic. -

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.1389_1390del; p.Val464GlyfsTer3 variant (rs80359283, ClinVar Variation ID: 51113), also known as 1617delAG, is reported in the literature in individuals affected with breast and/or ovarian cancer (selected references: Claes 2004, Foretova 2004, Goelen 1999, Momozawa 2018). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, 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: Claes K et al. BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. Br J Cancer. 2004 Mar 22;90(6):1244-51. PMID: 15026808. Foretova L et al. BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian cancer in the Czech Republic. Hum Mutat. 2004 Apr;23(4):397-8. PMID: 15024741. Goelen G et al. High frequency of BRCA1/2 germline mutations in 42 Belgian families with a small number of symptomatic subjects. J Med Genet. 1999 Apr;36(4):304-8. PMID: 10227398. Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. PMID: 30287823. -

Sep 01, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.1389_1390del (p.Val464Glyfs*3) variant (also known as 1617delAG) alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, this variant has been reported in multiple individuals with breast/ovarian cancer (PMIDs: 34490083 (2021), 31159747 (2019), 31263054 (2019), 30287823 (2018), 30322717 (2018), 26681312 (2015), 18489799 (2008), 16683254 (2006), 10227398 (1999)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Apr 19, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 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 been reported in at least 5 individuals affected with breast or ovarian cancer, including 2 male individuals (PMID: 21190077, 22711857, 24549055, 30287823, 34490083) and has been identified in 27 families among the CIMBA participants (PMID: 29446198). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 4/60466 cases and 2/53461 controls (OR=1.768 (95%CI 0.324 to 9.655); p-value=0.691) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001848). 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. -

Jan 09, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 28, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1389_1390delAG pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of two nucleotides between nucleotide positions 1389 and 1390, causing a translational frameshift with a predicted alternate stop codon (p.V464Gfs*3). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation was reported in one Belgian family affected with both breast and ovarian cancer (Goelen G et al. J. Med. Genet. 1999 Apr;36(4):304-8), one Japanese male breast cancer patient (Momozawa Y et al. Nat Commun. 2018 10;9:4083), and in Czech families considered high-risk for breast and ovarian cancer (Foretova L et al. Hum. Mutat. 2004 Apr;23(4):397-8; Machackova E et al. BMC Cancer 2008 May;8:140). This alteration was identified in 1/10,030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18:823-32). 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 1617delAG, c.1617_1618delAG, and c.1389_1390del2 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:2

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 2 nucleotide in exon 10 of the BRCA2 mRNA (c.1389_1390delAG), causing a frameshift after codon 464 and the creation of a premature translational stop signal 3 amino acid residues later (p.Val464Glyfs*3). This is expected to result in a truncated or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular truncation has been reported in the literature in families affected with breast and ovarian cancer (PMID: 10227398 ; Hum Mutat. 2004, 23:397-8; PMID: 16683254 ;PMID: 24549055). The mutation database ClinVar contains an entry for this variant (Variation ID: 51113). -

Jan 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Jul 01, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.1389_1390delAG (p.Val464GlyfsX3) 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 248414 control chromosomes (gnomAD). c.1389_1390delAG has been reported in the literature in multiple individuals affected with breast- and/or ovarian cancer (e.g. Goelen_1999, Foretova_2004, Claes_2004, Susswein_2015, Delgado_2011, Rebbeck_2018, Dorling_2021). 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. Eight 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. -

Dec 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val464Glyfs*3) 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: 10227398, 15024741, 16683254, 24549055, 26681312). This variant is also known as 1617delAG. ClinVar contains an entry for this variant (Variation ID: 51113). For these reasons, this variant has been classified as Pathogenic. -

BRCA2-related disorder Pathogenic:1

Mar 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1389_1390del;p.(Val464Glyfs*3) is a null frameshift variant (NMD) in the BRCA2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 51113; PMID: 10227398; PMID: 24549055; PMID: 16683254; PMID: 15024741; PMID: 26681312; PMID: 29446198). PS4. This variant is not present in population databases (rs80359283- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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: rs80359283; hg19: chr13-32907003; COSMIC: COSV104701258;