rs80359671

Positions:

• chr13-32331003-ACAAAT-A

Variant summary

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

The NM_000059.4(BRCA2):​c.771_775del​(p.Asn257LysfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,574 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:33 O:1
• Conservation: PhyloP100: 2.46

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 13-32331003-ACAAAT-A is Pathogenic according to our data. Variant chr13-32331003-ACAAAT-A is described in ClinVar as [Pathogenic]. Clinvar id is 9326.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32331003-ACAAAT-A is described in Lovd as [Pathogenic]. Variant chr13-32331003-ACAAAT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.771_775del	p.Asn257LysfsTer17	frameshift_variant	9/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.771_775del	p.Asn257LysfsTer17	frameshift_variant	9/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250748 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135542

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: 0.0000924

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460348 Hom.: 0 AF XY: 0.00000963 AC XY: 7 AN XY: 726556

Gnomad4 AFR exome AF: 0.0000299

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: 0.000150

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:33 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:15

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Dec 19, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 18, 2023	This variant deletes 5 nucleotides in exon 9 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 999del5 and 995delCAAAT in the literature. This variant is expected to result in an absent protein product and transient expression of this variant protein in ex vivo cells showed that it was unstable (PMID: 15217494). This variant has been reported as an Iceland founder mutation where it segregates with female and male breast cancer in families (PMID: 8673089, 9150155). This variant is found to confer risk for breast cancer and ovarian cancer (PMID: 12114473, 15571962, 16768547). Haplotype analysis also suggests there are two common haplotypes for this variant in Finnish breast cancer affected families (PMID: 11781689). This variant also has been observed in breast and ovarian cancer affected individuals and families in Austria, Egypt, France and South Korea (PMID: 23877192, 24156927, 24549055, 25863477). This variant has been identified in 2/250748 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. -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 09, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1; PM5_PTC_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 15, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_000059.4:c.771_775del (chr13:32331003) in BRCA2 was detected in 421 heterozygotes out of 58K WGS Icelanders (MAF= 0,363%). Following imputation in a set of 166K Icelanders (1,161 imputed heterozygotes) we observed an association with breast cancer using 6908 cases and 292623 controls (OR= 17.14, P= 1.37e-172). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	May 27, 2022	ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderated, PP1 strong -
Pathogenic, no assertion criteria provided	case-control	Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	May 24, 2021	- -
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. -
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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 09, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 29, 2020	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, the variant has been reported in individuals affected with breast cancer and has been described as a pathogenic founder variant in the Icelandic population (PMIDs: 31957001 (2020), 30093976 (2018), 23857704 (2013), and 17591843 (2007)). The frequency of this variant in the general population, 0.000092 (2/21636 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2023	Frameshift 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; Published functional studies demonstrate a damaging effect: shown in expression studies to be extremely unstable and to impact cytokinesis (Mikaelsdottir et al., 2004; Jonsdottir et al., 2009); Reported as a founder pathogenic variant in Iceland, accounting for 7-8% of all breast and ovarian cancer in the country (Johannesdottir et al., 1996; Thorlacius et al., 1997; Jonsdottir et al., 2009); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Tavtigian et al., 1996; Thorlacius et al., 1997; Azzollini et al., 2017; Chan et al., 2018; Bhaskaran et al., 2019); 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 999_1003del; This variant is associated with the following publications: (PMID: 28199346, 23857704, 8589730, 19478387, 8706004, 23747895, 9150155, 27537391, 28235830, 27062684, 29339979, 10807692, 30720243, 30702160, 30093976, 31159747, 31957001, 29625052, 26689913, 30787465, 31723001, 30350268, 31825140, 34254208, 32341426, 9802270, 30875412, 15571962, 34645131, 15217494) -

Hereditary breast ovarian cancer syndrome Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 06, 2023	Variant summary: BRCA2 c.771_775delTCAAA (p.Asn257LysfsX17) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250748 control chromosomes (gnomAD). c.771_775delTCAAA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Johannesdottir_1996 and Ingvarsson_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated variant affects normal protein expression (example: Mikaelsdottir_2004). The following publications have been ascertained in the context of this evaluation (PMID: 9766673, 8706004, 15217494). Eighteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Asn257Lysfs*17) 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 (rs80359671, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 8589730, 8673089, 9150155, 24549055, 25863477). It is commonly reported in individuals of Icelandic ancestry (PMID: 8673089, 9150155). This variant is also known as 999del5. ClinVar contains an entry for this variant (Variation ID: 9326). For these reasons, this variant has been classified as Pathogenic. -
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	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Sep 03, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	Founder variant in Icelanders -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This is a deletion of five base pairs, which results in frameshift and creation of a novel stop codon 17 amino acid residues later. The result is a truncated, non-functional protein. Truncating variants in BRCA2 are known to be pathogenic.This variant is also known as 999del5 in the literature and is a common cause of breast and ovarian cancer in the Icelandic population but has been reported also in individuals of other ethnicities (PMID: 9150155, 8673089, 8589730 ; 25863477 ).The mutation database Clinvar contains entries for this variant (Variation ID:9326). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 24, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 01, 2023	This variant deletes 5 nucleotides in exon 9 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 999del5 and 995delCAAAT in the literature. This variant is expected to result in an absent protein product and transient expression of this variant protein in ex vivo cells showed that it was unstable (PMID: 15217494). This variant has been reported as an Iceland founder mutation where it segregates with female and male breast cancer in families (PMID: 8673089, 9150155). This variant is found to confer risk for breast cancer and ovarian cancer (PMID: 12114473, 15571962, 16768547). Haplotype analysis also suggests there are two common haplotypes for this variant in Finnish breast cancer affected families (PMID: 11781689). This variant also has been observed in breast and ovarian cancer affected individuals and families in Austria, Egypt, France and South Korea (PMID: 23877192, 24156927, 24549055, 25863477). This variant has been identified in 2/250748 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2024	The c.771_775delTCAAA (p.N257Kfs*17) alteration, located in exon 9 (coding exon 8) of the BRCA2 gene, consists of a deletion of 5 nucleotides from position 771 to 775, causing a translational frameshift with a predicted alternate stop codon after 17 amino acids. 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 0.001% (2/250748) total alleles studied. The highest observed frequency was <0.001% (2/21636) of alleles. This alteration has been reported in several individuals diagnosed with breast and/or ovarian cancer (Tavtigian, 1996; Tryggvadottir, 2013; Azzollini, 2016; Sun, 2017). This mutation has been described as an Icelandic founder mutation accounting for 7-8% of female breast cancer and 40% of male breast cancer in Iceland (Thorlacius, 1997; Mikaelsdottir, 2004). One Icelandic study comparing breast cancer patients with and without this mutation suggests that estrogen receptor status in carrier individuals is a factor affecting prognosis (Jonasson, 2016). Of note, this alteration is also designated as 999del5 in published literature. Based on the available evidence, this alteration is classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Apr 02, 2020

- -

BRCA2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2024

The BRCA2 c.771_775del5 variant is predicted to result in a frameshift and premature protein termination (p.Asn257Lysfs*17). This variant (also reported as c.999del5) has been reported to be causative for breast and ovarian cancer (Tavtigian et al. 1996. PubMed ID: 8589730; Kang et al. 2015. PubMed ID: 25863477; Castéra et al. 2014. PubMed ID: 24549055) and is considered an Icelandic pathogenic founder variant associated with breast and ovarian cancers (Thorlacius et al. 1996. PubMed ID: 8673089; Thorlacius et al. 1997. PubMed ID: 9150155). This variant is reported in 0.0092% of alleles in individuals of European (Finnish) descent in gnomAD. Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 08, 2021

- -

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: rs80359671; hg19: chr13-32905140;