rs80359388

Variant names:

• chr13-32337898-ATT-A
• rs80359388
• NM_000059.4:c.3545_3546delTT

Your query was ambiguous. Multiple possible variants found:

• chr13-32337898-ATT-A
• chr13-32337898-ATT-AT

Variant summary

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

The NM_000059.4(BRCA2):​c.3545_3546delTT​(p.Phe1182fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,006 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: 0.000018 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:32
• Conservation: PhyloP100: 0.655

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 13-32337898-ATT-A is Pathogenic according to our data. Variant chr13-32337898-ATT-A is described in ClinVar as [Pathogenic]. Clinvar id is 37846.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337898-ATT-A is described in Lovd as [Pathogenic]. Variant chr13-32337898-ATT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.3545_3546delTT	p.Phe1182fs	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.3545_3546delTT	p.Phe1182fs	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.3176_3177delTT	p.Phe1059fs	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.3545_3546delTT		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250970 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135628

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: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461780 Hom.: 0 AF XY: 0.0000179 AC XY: 13 AN XY: 727178

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: 0.0000234

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:32

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:10

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 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 -

Nov 04, 2020

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; Observed as heterozygous in individuals with a personal and/or family history of BRCA2-related cancers, and as compound heterozygous in an individual with Fanconi anemia (Lubinski 2004, Cavallone 2010, Tea 2014, Belanger 2015, Malric 2015, Shindo 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3772delTT or 3773delTT; This variant is associated with the following publications: (PMID: 20104584, 21952622, 15131399, 25884701, 24156927, 21324516, 26986251, 25381700, 15382066, 20694749, 16905680, 28166811, 28767289, 21568838, 18042939, 17416853, 16825431, 16141007, 15796958, 15197194, 12677558, 9497246, 22430266, 26014432, 26295337, 29339979, 29084914, 30128899, 30609409, 30720243, 31851867, 31409081, 32255556) -

Nov 21, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 25, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.3545_3546delTT; p.Phe1182Ter variant (rs80359388), also known as 3772delTT and 3773delTT, has been reported in multiple individuals and families with breast, ovarian, and/or pancreatic cancer (Belanger 2015, Borg 2010, Cremin 2020, Labidi-Galy 2018, Lubinski 2004, Shindo 2017, Tea 2014). This variant is found on only five chromosomes (5/250970 alleles) in the Genome Aggregation Database. This variant deletes two nucleotides, induces an early termination codon and 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: Belanger MH et al. A targeted analysis identifies a high frequency of BRCA1 and BRCA2 mutation carriers in women with ovarian cancer from a founder population. J Ovarian Res. 2015 Mar 27;8:1. Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Cremin C et al. Burden of hereditary cancer susceptibility in unselected patients with pancreatic ductal adenocarcinoma referred for germline screening. Cancer Med. 2020 Jun;9(11):4004-4013. Labidi-Galy SI et al. Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer. Clin Cancer Res. 2018 Jan 15;24(2):326-333. Lubinski J et al. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3(1):1-10. Shindo K et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382-3390. Tea MK et al. Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. Maturitas. 2014 Jan;77(1):68-72. -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 2 nucleotide from exon 11 of the BRCA2 mRNA (c.3545_3546delTT), creating a premature translational stop signal at codon 1182 (p.Phe1182*). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This variant has been reported in the literature in individuals affected with breast and ovarian cancer (PMID: 15131399 24156927, 25884701, 20104584) and is also known as 3772delTT and c.3773delTT. The mutation database ClinVar contains entries for this variant (Variation ID: 37846). -

Aug 06, 2024

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, 0.000044 (5/113332 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant is also known as 3773delTT, and it has been reported in individuals affected with breast and/or ovarian cancer (PMID: 25884701 (2015), 21324516 (2011), 20694749 (2010), 20104584 (2010)). Based on the available information, this variant is classified as pathogenic. -

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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:9

May 04, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This BRCA2 variant (rs80359388) is rare (<0.1%) in a large population dataset (5/250970 total alleles; 0.002%; no homozygotes) and has an entry in ClinVar11. This nonsense variant, also known as 3772delTT and 3773delTT, has been reported in multiple unrelated individuals affected with hereditary breast and ovarian cancer. This frameshift variant creates a premature termination codon in exon 11 likely leading to nonsense-mediated decay and lack of protein production. We consider c.3545_3546del to be pathogenic. -

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2015

Institute of Human Genetics, Medical University Innsbruck

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 31, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 29, 2002

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

- -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

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. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Oct 14, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Phe1182X variant in BRCA2 has been reported in >20 individuals with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database (https://research.nhgri.nih.gov/bic/), Lubinski 2004 PMID: 15131399, Borg 2010 PMID: 20104584, Cavallone 2010 PMID: 20694749, Zhang 2011 PMID: 21324516, Finkelman 2012 PMID: 22430266, Tea 2014 PMID: 24156927, Belanger 2015 PMID: 25884701, Polsler 2016 PMID: 26014432, Shindo 2017 PMID: 28767289, Heramb 2018 PMID: 29339979, Labidi-Galy 2018 PMID: 29084914, Cremin 2020 PMID: 32255556). It has also been identified in 0.004% (5/113332) of 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 nonsense variant leads to a premature termination codon at position 1182, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. Furthermore, the p.Phe1182X variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282379.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP criteria applied: PVS1, PS4, PM2_Supporting. -

Jul 18, 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.3545_3546delTT (p.Phe1182X) 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 2e-05 in 250970 control chromosomes. c.3545_3546delTT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 27, 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.Phe1182*) 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 (rs748852670, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 15131399, 20104584, 24156927, 25884701). This variant is also known as 3772delTT, c.3773delTT, and p.Phe1182Terfs. ClinVar contains an entry for this variant (Variation ID: 37846). For these reasons, this variant has been classified as Pathogenic. -

Breast and/or ovarian cancer Pathogenic:2

Apr 28, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2016

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 13, 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 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 at least five individuals and in families affected with breast and/or ovarian cancer (PMID: 15131399, 15382066, 20104584, 20694749, 21324516, 24156927, 29084914, 29339979, 33471991; Leiden Open Variation Database DB-ID BRCA2_001009) and in an individual affected with Fanconi anemia with a family history of early-onset breast cancer (PMID: 25381700). This variant has been identified in 5/250970 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. -

Sep 13, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3545_3546delTT (p.F1182*) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of 2 nucleotides from position 3545 to 3546. This changes the amino acid from a phenylalanine to a stop codon at amino acid 1182. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.002% (5/250970) total alleles studied. The highest observed frequency was 0.004% (5/113332) of European (non-Finnish) alleles. This variant has been well described in the literature and has been seen in multiple individuals with a personal and/or family history consistent with hereditary breast and ovarian cancer (HBOC) syndrome, including several French-Canadian families (Lubinski, 2004; Oros, 2004; Simard, 2007; Borg, 2010; Borg, 2010; Belanger, 2015; Labidi-Galy, 2018). Of note, this alteration is also designated as 3773delTT and 3772delTT in published literature. Based on the available evidence, this alteration is classified as pathogenic. -

Carcinoma of pancreas Pathogenic:1

Mar 04, 2021

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

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 2 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 at least five individuals and in families affected with breast and/or ovarian cancer (PMID: 15131399, 15382066, 20104584, 20694749, 21324516, 24156927, 29084914, 29339979, 33471991; Leiden Open Variation Database DB-ID BRCA2_001009) and in an individual affected with Fanconi anemia with a family history of early-onset breast cancer (PMID: 25381700). This variant has been identified in 5/250970 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 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.3545_3546delTT variant is predicted to result in premature protein termination (p.Phe1182*). This variant, also known as 3772delTT and 3773delTT, has been reported in individuals with breast, ovarian, and pancreatic cancer (see for example - Lubinski et al. 2004. PubMed ID: 15131399; Shindo et al. 2017. PubMed ID: 28767289; Labidi-Galy et al. 2018. PubMed ID: 29084914, Table S2; Heramb et al. 2018. PubMed ID: 29339979). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in BRCA2 are expected to be pathogenic, and this variant has been classified as pathogenic by an expert panel in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/37846). 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

Mar 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Pathogenic:1

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Phe1182X variant has been identified in 4 out of 5086 proband chromosomes (frequency 0.001) in individuals with unilateral, contralateral and familial breast and ovarian cancer phenotype; however no control chromosomes were included in these studies (Lubinski 2004, Borg 2010). It is listed in dbSNP database coming from a “clinical source” (ID#: rs80359388) however no frequency information was provided. The variant was identified in ClinVar from 6 sources in at least 23 individuals from different ethnic backgroungs (GeneDx, BIC, Ambry, and SCRP derived from Myriad reports all classify this variant as pathogenic; Counsyl classified this variant as Likely pathogenic). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence and leads to a premature stop codon at position 1182. This alteration is predicted to cause a truncated or absent BRCA2 protein product and loss of function. Loss of function of the BRCA2 gene is an established disease mechanism in familial breast and ovarian cancer patients. In summary, based on the above information, this variant is classified as pathogenic. -

Familial cancer of breast Pathogenic:1

Mar 05, 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: rs80359388; hg19: chr13-32912035;