rs80359373

chr13-32337521-CAAAAG-C

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.3170_3174del(p.Lys1057ThrfsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000344 in 1,455,482 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. Q1056Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:24
• Conservation: PhyloP100: 4.11

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 13-32337521-CAAAAG-C is Pathogenic according to our data. Variant chr13-32337521-CAAAAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 37826.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337521-CAAAAG-C is described in Lovd as [Pathogenic]. Variant chr13-32337521-CAAAAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.3170_3174del	p.Lys1057ThrfsTer8	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.3170_3174del	p.Lys1057ThrfsTer8	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 246888 Hom.: 0 AF XY: 0.0000225 AC XY: 3 AN XY: 133440

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: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1455482 Hom.: 0 AF XY: 0.00000691 AC XY: 5 AN XY: 723456

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: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 23, 2016	- -
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	Sharing Clinical Reports Project (SCRP)	Jan 31, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant deletes 5 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3398del5 or 3398delAAAAG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in more than 15 individuals affected with breast or ovarian cancer (PMID: 16539696, 23479189, 23621881, 25863477, 26296701, 29084914, 33471991), in individuals affected with pancreatic cancer (PMID: 35547873) and in an individual affected with prostate cancer (PMID: 27433846). This variant has been identified in 3/246888 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	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	The c.3170_3174del (p.Lys1057Thrfs*8) variant in the BRCA2 gene has been detected in one family from a cohort of cancer patients [PMID 15131399, reported as 3398delAAAAG] and a cohort of patients with prostate cancer [PMID 27433846]. The variant was also reported in 11 patients in the Breast Cancer Information Core database. This 5 bp deletion in exon 11 results in a frameshift and the creation of a premature stop codon. This variant is thus predicted to result in a loss of function of the protein. This variant has been detected in three individuals in the ExAC database (http://exac.broadinstitute.org/variant/13-32911658-CAAAAG-C). This variant thus classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Lys1057Thrfs*8) 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 (rs781096360, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and pancreatic cancer (PMID: 15131399, 15382066, 16539696, 20694749, 23621881, 25863477, 25864590, 26296701, 27433846). This variant is also known as 3398delAAAAG and 3398del5. ClinVar contains an entry for this variant (Variation ID: 37826). 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	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 15, 2021	The p.Lys1057ThrfsX8 variant in BRCA2 is considered to be a founder variant in the French Canadian individuals with BRCA2-associated cancers (Oros 2006 PMID:16539696, Cavallone 2010 PMID:20694749, Ghadirian 2014 23621881) and has also been reported in affected individuals from other populations (Kang 2015 PMID:25863477, Sun 2017 PMID:28724667). This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1057 and leads to a premature termination codon 8 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 for hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on Sep 08, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 37826). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP criteria applied: PVS1, PS4, PM2_supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2022	Variant summary: BRCA2 c.3170_3174delAGAAA (p.Lys1057ThrfsX8) 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 1.2e-05 in 246888 control chromosomes. c.3170_3174delAGAAA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (eg. Lubinski_2004, Oros_2004, de Juan Jimenez_2013, Ghadirian_2013). 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. 14 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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 Molecular Medicine, Queen's University	Apr 20, 2017	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2021	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 individuals with hereditary breast and ovarian cancer and is considered a French Canadian pathogenic founder variant (Lubinski 2004, Oros 2006, Janavicius 2010, de Juan Jimenez 2013, Andrei 2015, Belanger 2015, Pritchard 2016); 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 3398del5; This variant is associated with the following publications: (PMID: 26296701, 25884701, 23199084, 25863477, 20694749, 28127413, 23479189, 25864590, 26941049, 27433846, 15382066, 16539696, 23621881, 15728167, 15131399, 29084914, 28724667, 30720243, 31447099) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 12, 2022	The BRCA2 c.3170_3174delAGAAA; p.Lys1057ThrfsTer8 variant (rs80359373), also known as 3398del5 in traditional nomenclature, has been reported in several individuals affected with breast or ovarian cancer (Ellingson 2015, Labidi-Galy 2018, Lubinski 2004, Kang 2015, Sun 2017). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37826) and is reported in the general population with an overall allele frequency of 0.001% (3/246888 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting five 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 to be pathogenic. References: Ellingson MS et al. Exome sequencing reveals frequent deleterious germline variants in cancer susceptibility genes in women with invasive breast cancer undergoing neoadjuvant chemotherapy. Breast Cancer Res Treat. 2015 Sep;153(2):435-43. 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. Kang E et al. The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. Breast Cancer Res Treat. 2015 May;151(1):157-68. Sun J et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 19, 2019	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported as a founder mutation in the French Canadian population (PMID: 23199084 (2010) and has been observed in affected individuals with breast, ovarian, prostate, and pancreatic cancer in the published literature (PMIDs: 15728167 (2005), 25864590 (2015), 26296701 (2015), 27433846 (2016), and 29084914 (2018)). Based on the available information, this variant is classified as pathogenic. -

Breast and/or ovarian cancer Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 09, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 20, 2023	This variant deletes 5 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3398del5 or 3398delAAAAG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in more than 15 individuals affected with breast or ovarian cancer (PMID: 16539696, 23479189, 23621881, 25863477, 26296701, 29084914, 33471991), in individuals affected with pancreatic cancer (PMID: 35547873) and in an individual affected with prostate cancer (PMID: 27433846). This variant has been identified in 3/246888 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	Apr 13, 2022	The c.3170_3174delAGAAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides between positions 3170 and 3174, causing a translational frameshift with a predicted alternate stop codon (p.K1057Tfs*8). This alteration is a known French Canadian founder mutation (Oros KK et al. BMC Med. Genet. 2006 Mar;7:23; Janavicius R. EPMA J. 2010 Sep;1:397-412) but has also been reported in multiple breast and/or ovarian cancer cohorts from various ethnicities (Lubinski J et al. Fam. Cancer. 2004;3:1-10; Ghadirian P et al. Clin. Genet. 2009 Nov;76:421-6; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Labidi-Galy SI et al. Clin. Cancer Res. 2018 01;24(2):326-333). This alteration was also identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53) and in a 47-year-old man diagnosed with pancreatic ductal adenocarcinoma (Andrei AZ et al. Cancer Lett. 2015 Aug;364:8-16). 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. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The BRCA2 p.Lys1057ThrfsX8 variant was identified in 26 of 11800 proband chromosomes (frequency: 0.002) from individuals or families with breast, ovarian, and metastatic prostate cancer (Lubinski 2004 PMID:15131399, Oros 2006 PMID:16539696, Oros 2004 PMID:15382066, Ghadirian 2009 PMID:19863560, Claus 2005 PMID:15728167, Pritchard 2016 PMID:27433846, Kang 2015 PMID:25863477, Belanger 2015 PMID:25884701). The variant was also identified in the following databases: dbSNP (ID: rs781096360) as “With Pathogenic allele”, ClinVar (14x as pathogenic by ENIGMA, CIMBA, Counsyl, COGR, Invitae, Ambry, GeneDx, Quest Diagnostics, Color Genomics, SCRP, BIC), Clinvitae (4x as pathogenic by ClinVar, Invitae), LOVD 3.0 (1x, with a pathogenicity prediction as "affects function"), UMD-LSDB (5 x as a causal variant), BIC Database (11x with clinical importance) and ARUP Laboratories (1x, as "5-definitely pathogenic"). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Databases. The variant was also identified by our laboratory in 8 individuals with breast or ovarian cancer. The p.Lys1057ThrfsX8 variant is described in the literature as a recurrent mutation in French Canadian cohorts, with haplotype analyses suggesting that this may be a founder mutation in this population (Oros 2004 PMID:15382066, Oros 2006 PMID:16539696, Ghadirian 2009 PMID:19863560, Janavicius 2010 PMID:23199084, Belanger 2015 PMID:25884701). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3170_3174del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1057 and leads to a premature stop codon, 8 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 BRCA2 related cancers 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 31, 2023

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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: rs80359373; hg19: chr13-32911658;