rs80359686

Positions:

• chr13-32362626-GCCTTT-G

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_7917del​(p.Phe2638Ter) 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. A2637A) has been classified as Likely benign. 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:26
• 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/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7913_7917del	p.Phe2638Ter	frameshift_variant	17/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7913_7917del	p.Phe2638Ter	frameshift_variant	17/27	5	NM_000059.4	A2

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:26

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1; PM2_supporting; PM5_PTC_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 28, 2023	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/). -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Apr 09, 2020	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 27, 2010	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2022	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 (Frank 1998, Balabas 2010, Becker 2012, Couch 2015, Wojcik 2016); Not observed 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 8138del5; This variant is associated with the following publications: (PMID: 25452441, 26843898, 28888541, 25893891, 20104584, 9667259, 24156927, 8988179, 22729890, 18465347, 20383589, 29339979, 31173646, 31209999, 31447099) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 07, 2020	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. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	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

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 16, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 07, 2017	- -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	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

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

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;