rs80359455

Variant names:

• chr13-32338827-TGAAA-T
• rs80359454
• NM_000059.4:c.4478_4481delAAAG

Variant summary

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

The NM_000059.4(BRCA2):​c.4478_4481delAAAG​(p.Glu1493ValfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000472 in 1,461,498 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: 0.000047 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:28
• Conservation: PhyloP100: 2.45

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 13-32338827-TGAAA-T is Pathogenic according to our data. Variant chr13-32338827-TGAAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 51653.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338827-TGAAA-T is described in Lovd as [Pathogenic]. Variant chr13-32338827-TGAAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.4478_4481delAAAG	p.Glu1493ValfsTer10	frameshift_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.4478_4481delAAAG	p.Glu1493ValfsTer10	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.4109_4112delAAAG	p.Glu1370ValfsTer10	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.4478_4481delAAAG		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250362 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135544

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461498 Hom.: 0 AF XY: 0.0000440 AC XY: 32 AN XY: 727050

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:28

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

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

- -

Sep 04, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

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. -

Feb 20, 2013

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Molecular Endocrinology Laboratory, Christian Medical College

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:7

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PVS1, PM2 -

Jan 28, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 hereditary breast and ovarian cancer (Tavtigian 1996, Meindl 2002, Zhang 2011, Kim 2012, Dudley 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 27488020, 27836010, 26681312, 29360161, 30720243, 28176296, 8589730, 11802209, 21324516, 22798144, 21952622, 26187060, 23569316, 10359546, 17148771, 9667259, 20927582, 16162645, 27225637, 29371908, 29478780, 29915322, 27153395, 11179017, 15131399, 30702160, 30322717, 32885271, 32338768) -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.4478_4481del; p.Glu1493ValfsTer10 variant (rs80359454), also known as 4706del for legacy nomenclature, is reported in multiple individuals and families with hereditary breast and ovarian cancer syndrome (Dudley 2018, Kote-Jarai 2011, Le 2022, Tavtigian 1996, Zhang 2011). This variant is also classified as pathogenic by an expert review panel in the ClinVar Database (Variation ID: 51653). It is observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting four 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: Dudley B et al. Germline mutation prevalence in individuals with pancreatic cancer and a history of previous malignancy. Cancer. 2018 Apr 15;124(8):1691-1700. PMID: 29360161. Kote-Jarai Z et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011 Oct 11;105(8):1230-4. PMID: 21952622. Le TN et al. BRCA1/2 Mutations in Vietnamese Patients with Hereditary Breast and Ovarian Cancer Syndrome. Genes (Basel). 2022 Jan 29;13(2):268. PMID: 35205313. Tavtigian SV et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996 Mar;12(3):333-7. PMID: 8589730. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. PMID: 21324516. -

Apr 20, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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 individuals and families affected with breast or ovarian cancer in the published literature (PMID: 27153395 (2016), 23884708 (2014), 22798144 (2012), 21952622 (2011), 21324516 (2011)). Based on the available information, this variant is classified as pathogenic. -

Nov 02, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu1493ValfsX10 variant in BRCA2 has been reported in >20 individuals with BRCA2-related cancers and segregated with disease in 12 individuals from one family (Tavtigian 1996, Kote-Jarai 2011, Zhang 2011, Maxwell 2016, Susswein 2016, Shi 2017, AlDubayan 2018, Dudley 2018, Mijuskovic 2018, BIC database). It has also been identified in 0.0035% (4/112994) European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1493 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. Additionally, this variant was classified as Pathogenic on Apr 22 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 51653). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PP1_Strong, PM2. -

Feb 02, 2025

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.Glu1493Valfs*10) 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 (rs776022857, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with female breast and ovarian cancer, male breast cancer, and prostate cancer (PMID: 8589730, 11179017, 15131399, 20927582, 21324516, 21952622, 22798144). This variant is also known as 4706del4. ClinVar contains an entry for this variant (Variation ID: 51653). For these reasons, this variant has been classified as Pathogenic. -

Apr 20, 2017

Department of Pathology and Molecular Medicine, Queen's University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA2 variant, c.4478_4481delAAAG (p.Glu1493Valfs), causes a frameshift resulting in a premature stop codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable clinical laboratories/databases cite the variant with a classification of "pathogenic." Therefore, the variant of interest is classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 11, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 4 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 reported in over 10 individuals affected with ovarian cancer (PMID: 11972384, 20406929, 21324516, 22711857, 23165508, 23791828, 23884708, 24728189), and individuals affected with breast cancer (PMID: 20950396, 22798144, 33758026, 33471991; Leiden Open Variation Database DB-ID BRCA2_001792, Color internal data). This variant has been identified in 4/250362 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. -

Jul 04, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4478_4481delAAAG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 4478 to 4481, causing a translational frameshift with a predicted alternate stop codon (p.E1493Vfs*10). This pathogenic mutation has been reported in multiple families affected with breast, ovarian and/or prostate cancer (Tavtigian SV et al. Nat. Genet., 1996 Mar;12:333-7; Frank TS et al. J Clin Oncol, 1998 Jul;16:2417-25; Risch HA et al. Am J Hum Genet, 2001 Mar;68:700-10; Lubinski J et al. Fam Cancer, 2004;3:1-10; Ding YC et al. Breast Cancer Res Treat, 2011 Apr;126:771-8; Zhang S et al. Gynecol Oncol, 2011 May;121:353-7; Kote-Jarai Z et al. Br J Cancer, 2011 Oct;105:1230-4; Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; McVeigh TP et al. Ir J Med Sci, 2014 Jun;183:199-206; Maxwell KN et al. Am J Hum Genet, 2016 May;98:801-817; Shi T et al. Int J Cancer, 2017 05;140:2051-2059; Dudley B et al. Cancer, 2018 04;124:1691-1700; Mijuskovic M et al. Br J Cancer, 2018 07;119:96-104; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149; Lattimore V et al. Breast Cancer Res Treat, 2021 Feb;185:583-590; Dorling et al. N Engl J Med. 2021 02;384:428-439). 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. -

Breast and/or ovarian cancer Pathogenic:1

Jun 01, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Jul 31, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM5_STR,PM2_SUP -

BRCA2-related cancer predisposition Pathogenic:1

Aug 19, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 4 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 reported in over 10 individuals affected with ovarian cancer (PMID: 11972384, 20406929, 21324516, 22711857, 23165508, 23791828, 23884708, 24728189), and individuals affected with breast cancer (PMID: 20950396, 22798144, 33758026, 33471991; Leiden Open Variation Database DB-ID BRCA2_001792, Color internal data). This variant has been identified in 4/250362 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. -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Malignant tumor of breast Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Glu1493Valfs*10 variant was identified in 12 of 17460 proband chromosomes (frequency: 0.0007) from individuals or families with prostate, breast or ovarian cancer (Beetstra 2006, Ding 2011, Fong 2010, Kim 2012, Kote-Jarai 2011, Lubinski 2004, Peto 1999, Risch 2001, Zhang 2011). The variant was also identified in dbSNP (ID: rs80359454) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and twelve other submitters), LOVD 3.0 (19x as pathogenic ), and UMD-LSDB (1x 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 variant was shown to have a partial response to platinum-based therapy according to the Response Evaluation Criteria in Solid Tumors and Gynecologic Cancer Intergroup Response criteria (Fong 2010). The c.4478_4481del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1493 and leads to a premature stop codon at position 1502. 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 (HBOC) 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

Jun 13, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diffuse intrinsic pontine glioma Pathogenic:1

Jun 09, 2017

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a frameshift alteration in which four nucleotides are deleted (coding nucleotides 4478 through 4481) and is predicted to change a Glutamic Acid to a Valine at amino acid codon 1493, shift the reading frame and result in a premature stop codon 10 amino acids downstream. Classification criteria: PVS1, PM2, PP1. -

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: rs80359454; hg19: chr13-32912964;