rs80359686

Variant names:

• chr13-32362626-GCCTTT-G
• rs80359686
• NM_000059.4:c.7913_7917delTTCCT

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.7913_7917delTTCCT​(p.Phe2638fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,862 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: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:28
• Conservation: PhyloP100: 7.93

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 13-32362626-GCCTTT-G is Pathogenic according to our data. Variant chr13-32362626-GCCTTT-G is described in ClinVar as [Pathogenic]. Clinvar id is 38126.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32362626-GCCTTT-G is described in Lovd as [Pathogenic]. Variant chr13-32362626-GCCTTT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7913_7917delTTCCT	p.Phe2638fs	frameshift_variant	Exon 17 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7913_7917delTTCCT	p.Phe2638fs	frameshift_variant	Exon 17 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7544_7548delTTCCT	p.Phe2515fs	frameshift_variant	Exon 17 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7921_7925delTTCCT		non_coding_transcript_exon_variant	Exon 16 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461862 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727228

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

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:10

Jul 01, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 08, 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. -

Nov 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with hereditary breast and ovarian cancer syndrome and is a known founder mutation (PMID: 20383589, 22729890, 22729890, 18489799, 23199084). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -

Sep 27, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 09, 2020

Division of Medical Genetics, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This deletion leads to a nonsense variant and the introduction of a premature termination codon. The variant is is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the literature in multiple individuals with breast or ovarian cancer (Balabas 2010, Becker 2012, Couch 2015, Wojcik 2016), and is reported to be a founder variant in the Czech population (Machachkova 2008, Janavicius 2010). This variant is not present in population databases (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PM2; PVS1 -

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

- -

Jan 04, 2018

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PM2_supporting; PM5_PTC_Strong -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:7

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 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; Reported in individuals with a personal and/or family history consistent with pathogenic variants in this gene (PMID: 9667259, 20383589, 22729890, 25452441, 26843898, 33471991); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8141_8145delTTCCT; 8138del5; c.7910_7914del5; This variant is associated with the following publications: (PMID: 25452441, 26843898, 25893891, 20104584, 9667259, 24156927, 8988179, 22729890, 18465347, 20383589, 29339979, 31173646, 31209999, 28888541, 31892343, 32629901, 31447099, 31723001, 15024741, 18489799, 24528374, 29446198, 34326862, 33670479, 33471991) -

Dec 05, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.7913_7917del; p.Phe2638Ter (also known as 8141del5) variant creates a frameshift and is predicted to result in a truncated protein or absent transcript. This variant has been described as a founder variant in the Czech population (Janavicius 2010, Machackova 2008), as well as reported several times in individuals and families with breast and ovarian cancer syndrome (Becker 2012, Wojcik 2016, see ClinVar link). This variant is listed in the dbSNP database (rs80359686), but is absent from the general population databases (Exome Variant Server, Genome Aggregation Database, 1000 Genomes Project). Taken together, this variant is considered pathogenic. References: Becker AA et al. A 24-color metaphase-based radiation assay discriminates heterozygous BRCA2 mutation carriers from controls by chromosomal radiosensitivity. Breast Cancer Res Treat. 2012 Aug;135(1):167-75. Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. EPMA J. 2010 Sep;1(3):397-412. Machackova E et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008 May 20;8:140. Wojcik P et al. Recurrent mutations of BRCA1, BRCA2 and PALB2 in the population of breast and ovarian cancer patients in Southern Poland. Hered Cancer Clin Pract. 2016 Feb 3;14:5. -

Jul 03, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Apr 10, 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.7913_7917delTTCCT (p.Phe2638X) 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 251282 control chromosomes. c.7913_7917delTTCCT 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 other ClinVar submitters (evaluation after 2014) have cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 22, 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.Phe2638*) 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: 8988179, 15024741, 18489799, 22729890, 24528374). It has also been observed to segregate with disease in related individuals. This variant is also known as 8138del5. ClinVar contains an entry for this variant (Variation ID: 38126). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Dec 07, 2017

True Health Diagnostics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 5 nucleotides in exon 17 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 is also known as 8141del5 in the literature. This variant has been reported in more than 10 individuals affected with breast or ovarian cancer (PMID: 20383589, 22729890, 24528374, 26843898, 31173646, 33471991, 33670479) and has been identified in 37 families among the CIMBA participants (PMID: 29446198). 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. -

Sep 30, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7913_7917delTTCCT pathogenic mutation (also known as p.F2638*), located in coding exon 16 of the BRCA2 gene, results from a deletion of five nucleotides between positions 7913 and 7917. This changes the amino acid from a phenylalanine to a stop codon within coding exon 16. This mutation has been identified in numerous families with breast and/or ovarian cancer (Gayther SA et al. Nat. Genet., 1997 Jan;15:103-5; Frank TS et al. J Clin Oncol, 1998 Jul;16:2417-25; Balabas A et al. Fam Cancer, 2010 Sep;9:267-74; Becker AA et al. Breast Cancer Res. Treat., 2012 Aug;135:167-75; Wojcik P et al. Hered Cancer Clin Pract, 2016 Feb;14:5; Cybulski C et al. Int J Cancer, 2019 12;145:3311-3320; ukomska A et al. Cancers (Basel), 2021 Feb;13; Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was identified multiple times in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). A Czech founder effect was recognized in one study (Machackova E et al. BMC Cancer 2008 May;8:140). Of note, this alteration is also designated as 8141del5 and 8138del5 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

Mar 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a deletion of 5 base pairs amino resulting in an amino acid change from Phenylalanine to a Termination codon at amino acid residue 2638 of the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This particular truncation has been reported in the literature as 8141del5 and has been reported in families and patients with breast and/or ovarian cancer (PMID: 9667259, 20383589). This variant has also been described as a founder mutation in the Czech population (PMID: 23199084). -

Breast and/or ovarian cancer Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

BRCA2-related disorder Pathogenic:1

Aug 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.7913_7917del5 variant is predicted to result in premature protein termination (p.Phe2638*). This variant is also referred to as 8138del5 or 8141del5 in the literature. It has been reported in many individuals with breast and/or ovarian cancer (see, for example, Gayther et al. 1997. PubMed ID: 8988179; Becker et al. 2012. PubMed ID: 22729890; Łukomska et al. 2021. PubMed ID: 33670479). It has been described as a founder variant in the Czech population (Machackova et al. 2008. PubMed ID: 18489799). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, it is classified as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/38126/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80359686; hg19: chr13-32936763;