rs80359527

Variant names:

• chr13-32340035-T-TA
• rs80359527
• NM_000059.4:c.5681dupA

Your query was ambiguous. Multiple possible variants found:

• chr13-32340035-T-TA
• chr13-32340035-T-TAA

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.5681dupA​(p.Tyr1894fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,344 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. Y1894Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift, stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:20
• Conservation: PhyloP100: -1.57

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 13-32340035-T-TA is Pathogenic according to our data. Variant chr13-32340035-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 37988.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5681dupA	p.Tyr1894fs	frameshift_variant, stop_gained	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.5681dupA	p.Tyr1894fs	frameshift_variant, stop_gained	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5312dupA	p.Tyr1771fs	frameshift_variant, stop_gained	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5681dupA		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250446 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

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: 0.00000205 AC: 3 AN: 1461344 Hom.: 0 Cov.: 45 AF XY: 0.00000275 AC XY: 2 AN XY: 726968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

Submissions by phenotype

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

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

- -

Jul 19, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts an adenine nucleotide into exon 11 creating a premature stop signal. To our knowledge, functional studies have not been reported for this variant. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 16683254, 17851763, 27153395, 28947987, 28294317, 28724667, 28993434, 29907814). This variant has been identified in 1/250446 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. -

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

- -

Nov 29, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 31, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Pathogenic:5

Mar 21, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.5681dup (p.Tyr1894*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 36537080 (2023), 30720863 (2019), 30322717 (2018), 28993434 (2018), 18042939 (2007)). The frequency of this variant in the general population, 0.000054 (1/18390 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 20, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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; 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 5909dup; This variant is associated with the following publications: (PMID: 26852015, 15131399, 17851763, 17922257, 29310832, 32879886, 35957908, 36367610, 11241844, 18042939, 21324516, 10550133, 27356891, 16683254, 11897832, 23961350, 27721756, 29061375, 29907814, 23697973, 28724667, 28993434, 30720863, 30720243, 30702160, 30322717, 31447099, 34399810, 31825140, 30787465, 32467295, 33151324, 29922827, 35864222, 33461583) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PVS1, PM2, PS4:Moderate -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Oct 14, 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.Tyr1894*) 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 (rs80359527, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11241844, 16683254, 23697973). This variant is also known as 5909insA. ClinVar contains an entry for this variant (Variation ID: 37988). For these reasons, this variant has been classified as Pathogenic. -

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

- -

Sep 03, 2020

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.5681dupA (p.Tyr1894X) 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 4e-06 in 250446 control chromosomes. c.5681dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples Hamann_2002, Tai_2007, Solano_2012, 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. Ten other ClinVar submitters (evaluation after 2014) have cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 12, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr1894X variant in BRCA2 has been reported in at least 8 individuals here ditary breast and or ovarian cancer (HBOC; Edwards 2001, Li 2008, Solano 2012, B reast Cancer Information Core (BIC) database) and one individual with unknown cl inical status with a possible history of familial breast and/or ovarian cancer w ho underwent genetic screening for BRCA1 and BRCA2 (van der Hout 2006). It was a lso identified in 1/17242 of East Asian chromosomes by the Genome Aggregation Da tabase (gnomAD; http://gnomad.broadinstitude.org; dbSNP rs80359527); however, th is frequency is low enough to be consistent with the frequency of HBOC in the ge neral population. This nonsense variant is a result of a duplication of one base pair at position 5681, which creates a premature termination codon at amino aci d position 1894. This alteration is then predicted to lead to a truncated or abs ent protein. Heterozygous loss of function of the BRCA2 gene is an established d isease mechanism in hereditary breast and ovarian cancer. Moreover, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA e xpert panel (SCV000282411.1). In summary, this variant meets criteria to be clas sified as pathogenic for hereditary breast and ovarian cancer in an autosomal do minant manner based upon predicted impact on the protein, presence in multiple a ffected individuals and low frequency in controls. -

Hereditary cancer-predisposing syndrome Pathogenic:2

May 08, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 16683254, 17851763, 27153395, 27463008, 28294317, 28724667, 28993434, 29907814). This variant has been identified in 1/250446 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. -

Apr 05, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5681dupA pathogenic mutation (also known as p.Y1894*), located in coding exon 10 of the BRCA2 gene, results from a duplication of A at position 5681. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This pathogenic mutation has been previously reported in Asian, European, and South American breast/ovarian cohorts (van der Hout AH et al. Hum. Mutat. 2006 Jul;27(7):654-66; Li WF et al. Breast Cancer Res. Treat. 2008 Jul;110(1):99-109; Solano AR et al. Springerplus. 2012 Sep;1:20; Castro M et al. Case Rep. Oncol. 2016 Jul;9(2):387-394; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103; Palmero EI et al. Sci. Rep. 2018 Jun;8(1):9188). Of note, this alteration is also designated as 5909insA 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, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs80359527; hg19: chr13-32914172;