rs770318608

chr13-32339928-CAATT-C

Variant summary

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

The NM_000059.4(BRCA2):c.5576_5579del(p.Ile1859LysfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,605,350 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. T1858T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:36 O:1
• Conservation: PhyloP100: 1.16

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 13-32339928-CAATT-C is Pathogenic according to our data. Variant chr13-32339928-CAATT-C is described in ClinVar as [Pathogenic]. Clinvar id is 37975.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339928-CAATT-C is described in Lovd as [Pathogenic]. Variant chr13-32339928-CAATT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5576_5579del	p.Ile1859LysfsTer3	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5576_5579del	p.Ile1859LysfsTer3	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151950 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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: 0.0000163 AC: 4 AN: 244832 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132392

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000193 AC: 28 AN: 1453400 Hom.: 0 AF XY: 0.0000194 AC XY: 14 AN XY: 722240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151950 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74194

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:36 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2019	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; Observed in a multiple individuals with a personal or family history consistent with pathogenic variants in this gene (Ikeda 2001, Sugano 2008, Wang 2012, Kang 2015, Kim 2016, Eoh 2017, Pritzlaff 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 c.5574_5577delAATT or 5804del4; This variant is associated with the following publications: (PMID: 22160602, 23683081, 22798144, 28127413, 28541631, 30203341, 11149425, 8705994, 25863477, 23633455, 19016756, 22713736, 24578176, 26848529, 27914478, 28008555, 27633797, 24094589, 28166811, 29422015, 26681312, 28724667, 29348823, 29020732, 29360550, 21643751, 29752822, 29673794, 30287823, 28111427, 30720243, 30742731, 30702160, 30322717, 31143373, 30309222, 31666926, 32300630, 30291343, 29625052, 26689913, 30350268, 31447099, 29176636, 31214711) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	The BRCA2 c.5576_5579delTTAA; p.Ile1859LysfsTer3 variant (rs80359520), also reported as 5802del4, 5803del4 and 5804del4, has been described in the literature in several individuals and families with breast and ovarian cancer (Foster 1996, George 2013, Schneegans 2012). This variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37975) and is found in the general population with an overall allele frequency of 0.002% (4/244832 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information this variant is considered pathogenic. References: Foster KA et al. Somatic and germline mutations of the BRCA2 gene in sporadic ovarian cancer. Cancer Res. 1996 56(16):3622-5. George J et al. Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations. Clin Cancer Res. 2013 19(13):3474-84. Schneegans SM et al. Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Fam Cancer. 2012 11(2):181-8. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 12, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 14, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 09, 2023	The BRCA2 c.5576_5579del (p.Ile1859Lysfs*3) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals and families with breast/ovarian cancer (PMIDs: 35918668 (2022), 34645131 (2022), 31143373 (2019), 30287823 (2018), 23683081 (2013), 23633455 (2013), 22713736 (2012), 22217648 (2012), 22160602 (2012), 20104584 (2010)), and biliary track cancer (PMIDs: 32918181 (2021), 31666926 (2019)). The frequency of this variant in the general population, 0.000016 (4/244832 chromosomes (Genome Aggregation Database, 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	Mayo Clinic Laboratories, Mayo Clinic	Oct 12, 2020	PVS1, PM2, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant as also known as 5802delTTAA, 5803delATTA, 5804_5808delTTAA, 5804del4 and c.5574_5577delAATT in the literature. This variant is expected to result in unstable variant messenger RNA, which is corroborated by an RNA analysis of allelic imbalance in expressed BRCA2 mRNA transcripts in a heterozygous variant carrier (PMID: 19471317). This variant has been reported in over 30 individuals affected with breast and ovarian cancer (PMID: 8705994, 11149425, 17262179, 20104584, 21233401, 22160602, 22713736, 22798144, 23479189, 23633455, 23683081, 24249303, 24578176, 24728189, 26848529). A Japanese breast cancer case-control study (PMID: 30287823) and a breast cancer case-control meta-analysis (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001464) have reported this variant in 27/7104 cases and 3/23731 unaffected controls and 16/60450 cases and 7/53454 unaffected controls, respectively. This variant also has been reported in a prostate cancer case-control study in 11/7636 prostate cancer cases and 2/12366 unaffected controls (PMID: 31214711). This variant has been identified in 4/244832 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	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Pathogenic, criteria provided, single submitter	research	Laan Lab, Human Genetics Research Group, University of Tartu	May 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 25, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -
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 Medical Genetics, Oslo University Hospital	Jan 10, 2017	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Ile1859Lysfs*3) 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 (rs770318608, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8705994, 22160602, 22217648, 23633455, 23683081). This variant is also known as 5803delATTA, 5804del4, and 5574_5577delAATT. ClinVar contains an entry for this variant (Variation ID: 37975). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2016	Variant summary: The c.5576_5579delTTAA variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.5585_5588delTGAA, c.5603_5606delACAG, c.5616_5620delAGTAA). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.003% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant has been cited in numerous affected individuals via the literature and databases, and has been classified by multiple reputable databases and clinical labs as "pathogenic". Taken together, this variant has been classified as 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 15, 2021	The p.Ile1859LysfsX3 variant in BRCA2 has been reported in >35 individuals with BRCA2-associated cancers (Saghir 2015 PMID:25777348, Kim 2016 PMID:26848529, Breast Cancer Information Core database (BIC): https://research.nhgri.nih.gov/bic/). It has also been identified in 0.002% (1/41368) African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1859 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in HBOC. Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variant ID 37975). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP criteria applied: PS4, PM2_Supporting, PVS1. -

Familial cancer of breast Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	Center for Precision Medicine, Meizhou People's Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 08, 2023	- -
Pathogenic, no assertion criteria provided	research	Department of Medical Laboratory Science, Faculty of Allied Health Sciences, University of Peradeniya	Oct 19, 2019	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jul 12, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 13, 2023	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 5802delTTAA, 5803delATTA, 5804_5808delTTAA, 5804del4 and c.5574_5577delAATT in the literature. This variant is expected to result in unstable variant messenger RNA, which is corroborated by an RNA analysis of allelic imbalance in expressed BRCA2 mRNA transcripts in a heterozygous variant carrier (PMID: 19471317). This variant has been reported in over 30 individuals affected with breast and ovarian cancer (PMID: 8705994, 11149425, 17262179, 20104584, 21233401, 22160602, 22713736, 22798144, 23479189, 23633455, 23683081, 24249303, 24578176, 24728189, 26848529). A Japanese breast cancer case-control study (PMID: 30287823) and a breast cancer case-control meta-analysis (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001464) have reported this variant in 27/7104 cases and 3/23731 unaffected controls and 16/60450 cases and 7/53454 unaffected controls, respectively. This variant also has been reported in a prostate cancer case-control study in 11/7636 prostate cancer cases and 2/12366 unaffected controls (PMID: 31214711). This variant has been identified in 4/244832 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	Jan 17, 2022	The c.5576_5579delTTAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5576 to 5579, causing a translational frameshift with a predicted alternate stop codon (p.I1859Kfs*3). This mutation has been reported in numerous hereditary breast and ovarian cancer (HBOC) patients and families world-wide (Foster KA et al. Cancer Res. 1996 Aug;56:3622-5; Gonzalez-Angulo AM et al. Clin. Cancer Res. 2011 Mar;17:1082-9; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Blay P et al. BMC Cancer. 2013 May;13:243; George J et al. Clin. Cancer Res. 2013 Jul;19:3474-84; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Kim YC et al. Oncotarget. 2016 Feb;7:9600-12; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Maistro S et al. BMC Cancer. 2016 Dec;16:934; Zhao Q et al. J. Gynecol. Oncol. 2017 Jul;28:e39; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Liang Y et al. Med Sci Monit, 2018 Apr;24:2465-2475; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Sunami K et al. Cancer Sci, 2019 Apr;110:1480-1490; Yoshida R et al. Oncotarget, 2019 May;10:3276-3284; Ueda M et al. Obstet Gynecol Int, 2019 May;2019:4365754; El Ansari FZ et al. BMC Cancer, 2020 Aug;20:747; Park CS et al. Asian J Surg, 2020 Oct;43:996-1001; Sirisena N et al. Breast Cancer Res, 2020 05;22:43; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Bang YJ et al. Cancer Res Treat, 2021 Oct). This mutation has also been identified in patients diagnosed with prostate and biliary tract cancer (Wardell CP et al. J Hepatol, 2018 05;68:959-969; Terashima T et al. Oncotarget, 2019 Oct;10:5949-5957; Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376; Power R et al. Fam Cancer, 2021 04;20:97-101). Of note, this alteration is also designated as c.5574_5577delAATT, 5803delATTA and 5804del4 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. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Mar 10, 2009

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Ile1859Lysfs*3 variant was identified in 72 of 57,640 proband chromosomes (freq: 0.001) from individuals or families with breast or ovarian cancer and in 3 of 47,462 chromosomes (freq: 0.00006) from healthy individuals (Momozawa 2018, Bhaskaran 2019, George 2013, Foster 1996, Haeyoun 2012, Kokichi 2008, Jalkh 2012, Schneegans 2012, Jang 2012, Blay 2013). The variant was identified in dbSNP (rs1255151416) as “NA”, ClinVar (classified as pathogenic by Invitae, Ambry Genetics, Color, GeneDx and 17 other submitters), LOVD 3.0 (observed 35x) and UMD-LSDB (observed 26x). The variant was identified in control databases in 4 of 244,832 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15,994 chromosomes (freq: 0.0001), European in 2 of 111,564 chromosomes (freq: 0.00002), and East Asian in 1 of 18,154 chromosomes (freq: 0.00006); it was not observed in the Latino, Ashkenazi Jewish, South Asian, Finnish, or Other populations. The p.Ile1859Lysfs*3 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1859 and leads to a premature stop codon 3 codons downstream. This alteration is then predicted to result in 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. -

Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

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: rs80359520; hg19: chr13-32914065;