rs80359484

Variant names:

• chr13-32339482-TTATG-T
• rs80359484
• NM_000059.4:c.5130_5133delTGTA

Variant summary

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

The NM_000059.4(BRCA2):​c.5130_5133delTGTA​(p.Tyr1710fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000699 in 1,430,836 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: 33)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:24
• Conservation: PhyloP100: 2.09

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 13-32339482-TTATG-T is Pathogenic according to our data. Variant chr13-32339482-TTATG-T is described in ClinVar as [Pathogenic]. Clinvar id is 51775.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339482-TTATG-T is described in Lovd as [Pathogenic]. Variant chr13-32339482-TTATG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5130_5133delTGTA	p.Tyr1710fs	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.5130_5133delTGTA	p.Tyr1710fs	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.4761_4764delTGTA	p.Tyr1587fs	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5130_5133delTGTA		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000441 AC: 1 AN: 226864 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 122978

Gnomad AFR exome AF: 0.0000655

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000699 AC: 10 AN: 1430836 Hom.: 0 AF XY: 0.00000704 AC XY: 5 AN XY: 709840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000546

Gnomad4 OTH exome AF: 0.0000339

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

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. -

Sep 13, 2010

Sharing Clinical Reports Project (SCRP)

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

- -

Mar 08, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2014

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

- -

not provided Pathogenic:5

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a deletion of 4 base pairs, which results in frameshift and creation of a new stop codon at amino acid residue 1710 of the BRCA2 gene. This is expected to result in an absent or disrupted protein product. Truncating variants in the BRCA2 gene are known to be pathogenic. This variant has been described in mutation databases as 5358_5361delTGTA, 5358delTGTA, or 5358del4. The mutation database ClinVar contains an entry for this variant (Variation ID: 51775). -

Dec 15, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Tyr1710* variant was identified in 22 of 48352 proband chromosomes (frequency: 0.0005) from individuals or families with hereditary breast and ovarian cancer (Rebbeck 2018, Soumittra 2009, Wong-Brown 2015, Bhaskaran 2019, Friedman 1997, de Juan Jimenez 2013, Shirts 2016, Fackenthal 2012, Finkelman 2012, Thomassen 2008, Ramus 2007). The variant was identified in dbSNP (rs760558178) as “NA”, ClinVar (classified as pathogenic by Invitae, Ambry Genetics, Color, GeneDx and 11 other submitters), LOVD 3.0 (observed 18x) and UMD-LSDB (observed 10x). The variant was identified in control databases in 1 of 226,864 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 1 of 15268 chromosomes (freq: 0.00007), while it was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, European, Other or South Asian populations. The c.5130_5133del variant leads to a premature stop codon at position 1710, which is predicted to lead to 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. -

Jul 16, 2021

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 a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established consortium and/or database; Also known as 5358_5361delTGTA, 5358delTGTA, or 5358del4; This variant is associated with the following publications: (PMID: 29176636, 31447099, 26689913, 29625052, 31721781, 17688236, 30322717, 30702160, 30720243, 27989354, 28831036, 28127413, 26845104, 28008555, 24249303, 26586665, 26187060, 25682074, 19656415, 23479189, 9012404, 22430266, 18465347, 20665887, 22034289, 31060517) -

Feb 16, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.0000044 (1/226864 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2), 32885271 (2020), 31825140 (2020), 30130155 (2018), 30322717 (2018), 29625052 (2018), 28888541 (2017), 26689913 (2015), 28008555 (2017), 26845104 (2016), 26586665 (2015)), prostate cancer (PMIDs: 33804961 (2021), 27989354 (2017)), pancreatic cancer (PMID: 32980694 (2020)), and healthy individuals (PMIDs: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2), 33804961 (2021), 32719484 (2020), 31447099 (2019)). Based on the available information, this variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Apr 20, 2017

Department of Pathology and Molecular Medicine, Queen's University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr1710X variant in BRCA2 has been reported in >15 individuals with BRCA2-related cancers (Friedman 1997 PMID: 9012404, Soumittra 2009 PMID: 19656415, de Juan Jiménez 2013 PMID: 23479189, Wong-Brown 2015 PMID: 25682074, Maxwell 2017 PMID: 28831036, Na 2017 PMID: 27989354, Pritzlaff 2017 PMID: 28008555, breast cancer information core (BIC) database: https://research.nhgri.nih.gov/bic/). It has also been identified in 0.0065% (1/15268) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This nonsense is a result of a deletion of 4 bases (c.5130_5133delTGTA), which creates a premature termination codon at amino acid position 1710. 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: 51775). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PVS1. -

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

- -

Jan 15, 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.Tyr1710*) 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 (rs760558178, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 9012404, 19656415, 23479189, 25682074, 26586665, 26845104). This variant is also known as 5358del4 and p.Tyr1693X. ClinVar contains an entry for this variant (Variation ID: 51775). For these reasons, this variant has been classified as Pathogenic. -

Apr 06, 2018

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.5130_5133delTGTA (p.Tyr1710X) 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 4.5e-06 in 222984 control chromosomes. c.5130_5133delTGTA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Friedman 1997, Ramus 2007, Thomassen 2008, Soumittra 2009, Fackenthal 2012). 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. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jul 02, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5130_5133delTGTA pathogenic mutation (also known as p.Y1710*), located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5130 to 5133. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This alteration has been reported in numerous breast and/or ovarian cancer cohorts (Friedman LS et al. Am. J. Hum. Genet. 1997 Feb;60:313-9; Soumittra N et al. Hered. Cancer Clin. Pract. 2009 Aug;7:13; de Juan Jiménez I et al. Fam. Cancer. 2013 Dec;12:767-77; Nakamura S et al. Breast Cancer. 2015 Sep;22:462-8; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 5358del4 and c.5129_5132delATGT 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. -

Jan 16, 2024

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 also known as c.5129_5132delATGT, 5358delTGTA and 5357del4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 15 individuals affected with breast and/or ovarian cancer (PMID: 9012404, 17688236, 19656415, 21720365, 22034289, 23479189, 24249303, 25682074, 26845104, 28008555, 28294317, 33471991; Leiden Open Variation Database DB-ID BRCA2_001903). This variant has been identified in 1/226864 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. -

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

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related cancer predisposition Pathogenic:1

Jul 29, 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 also known as c.5129_5132delATGT, 5358delTGTA and 5357del4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 15 individuals affected with breast and/or ovarian cancer (PMID: 9012404, 17688236, 19656415, 21720365, 22034289, 23479189, 24249303, 25682074, 26845104, 28008555, 28294317, 33471991; Leiden Open Variation Database DB-ID BRCA2_001903). This variant has been identified in 1/226864 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. -

BRCA2-related disorder Pathogenic:1

Mar 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.5130_5133delTGTA variant is predicted to result in premature protein termination (p.Tyr1710*). This variant has been reported in individuals with breast and ovarian cancer (male patient, Friedman et al. 1997. PubMed ID: 9012404; Table S1, Carter et al. 2018. PubMed ID: 30322717; de Juan Jiménez et al. 2013. PubMed ID: 23479189). This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51775/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

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Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PM2_Supporting+PS4_Moderate -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial cancer of breast Pathogenic:1

Mar 25, 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: rs80359484; hg19: chr13-32913619;