rs80359489

chr13-32339511-A-AT

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.5158dup(p.Ser1720PhefsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 0.483

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 13-32339511-A-AT is Pathogenic according to our data. Variant chr13-32339511-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 51781.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5158dup	p.Ser1720PhefsTer7	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5158dup	p.Ser1720PhefsTer7	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Ser1720Phefs*7) 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/or ovarian cancer (PMID: 21324516, 25395318, 26219728). This variant is also known as c.5158_5159insT and 5386insT. ClinVar contains an entry for this variant (Variation ID: 51781). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 02, 2021	Variant summary: BRCA2 c.5158dupT (p.Ser1720PhefsX7) 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 228554 control chromosomes. c.5158dupT 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. Multiple clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4

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)	Feb 20, 2004	- -
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, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 12, 2012	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2022	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 a personal or family history consistent with pathogenic variants in this gene (Zhang et al., 2011; Coppa et al., 2014; Finch et al., 2015); Not observed at significant frequency 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 5386dupT; This variant is associated with the following publications: (PMID: 19714488, 25186627, 28888541, 25395318, 21324516, 26219728, 28152038, 32438681, 30787465, 29446198) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 30, 2020	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals with breast and/or ovarian cancer in the published literature (PMID: 25186627 (2015), 25395318 (2014), 21324516 (2011), 19714488 (2009)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 21, 2022	The BRCA2 c.5158dupT; p.Ser1720PhefsTer7 variant (rs80359489), also known as 5386dup in traditional nomenclature, is reported in the literature in several individuals and families affected with breast and/or ovarian cancer (Coppa 2014, Finch 2016, Rebbeck 2018, Santonocito 2020, Tung 2015). This variant is also reported in ClinVar (Variation ID: 51781) and is classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, 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: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ Coppa A et al. Novel and recurrent BRCA2 mutations in Italian breast/ovarian cancer families widen the ovarian cancer cluster region boundaries to exons 13 and 14. Breast Cancer Res Treat. 2014 Dec;148(3):629-35. PMID: 25395318. Finch A et al. Genetic testing for BRCA1 and BRCA2 in the Province of Ontario. Clin Genet. 2016 Mar;89(3):304-11. PMID: 26219728. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. PMID: 29446198. Santonocito C et al. Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. Cancers (Basel). 2020 May 19;12(5):1286. PMID: 32438681. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. PMID: 25186627. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 29, 2020	This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 19714488, 21324516, 25186627, 25395318, 26219728, 32438681). 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, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 17, 2021	The c.5158dupT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 5158, causing a translational frameshift with a predicted alternate stop codon (p.S1720Ffs*7). This mutation has been reported in an individual of Italian descent from a cohort of 1342 unselected women with invasive epithelial ovarian tumors (Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7). This alteration was detected in a breast-ovarian cancer family from Italy and resides in the ovarian cancer cluster region (OCCR) of BRCA2 (Coppa A et al. Breast Cancer Res.Treat. 2014 Dec;148(3):629-35). This alteration was also detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 of Western/ Northern European ancestry. (Tung N et al. Cancer. 2015 Jan;121:25-33). Of note, this alteration is also referred to as 5386insT and c.5158_5159insT in the published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 01, 2022

- -

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: rs80359489; hg19: chr13-32913648;