chr13-32340011-C-T

Variant names:

• chr13-32340011-C-T
• rs80358790
• NM_000059.4:c.5656C>T

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.5656C>T​(p.Gln1886*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: -0.00100

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 13-32340011-C-T is Pathogenic according to our data. Variant chr13-32340011-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 51900.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340011-C-T is described in Lovd as [Pathogenic]. Variant chr13-32340011-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5656C>T	p.Gln1886*	stop_gained	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5656C>T	p.Gln1886*	stop_gained	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5287C>T	p.Gln1763*	stop_gained	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5656C>T		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

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

Aug 16, 2000

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

Apr 16, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Dec 06, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This pathogenic variant is denoted BRCA2 c.5656C>T at the cDNA level and p.Gln1886Ter (Q1886X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also known as BRCA2 5884C>T using alternate nomenclature, has been reported in Korean individuals with breast cancer (Seong 2009, Kim 2012, Kang 2015) and is considered pathogenic. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Gln1886X variant was identified in 5 of 8256 proband chromosomes (frequency: 0.001) from individuals with breast or ovarian cancer (Kim 2012, Seong 2009). The variant was also identified in dbSNP (ID: rs80358790) “With untested allele”, HGMD, LOVD, COSMIC, UMD (2X as a causal variant), and the BIC database (2X with clinical importance). The p.Gln1886X variant leads to a premature stop codon at position 1886, which is predicted to lead to 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. -

Jul 05, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.5656C>T (p.Gln1886*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMID: 19656164 (2009), 22798144 (2012), 25863477 (2015), 30309222 (2019)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect BRCA2 mRNA splicing. Based on the available information, this variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Aug 07, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.5656C>T (p.Gln1886X) 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 was absent in 249626 control chromosomes. c.5656C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Seong_2009, Kang_2012, Kim_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19656164, 22798144, 22438049). Seven 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. -

Apr 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln1886*) 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 cancer (PMID: 19656164, 29446198). ClinVar contains an entry for this variant (Variation ID: 51900). For these reasons, this variant has been classified as Pathogenic. -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 12, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1886* pathogenic mutation (also known as c.5656C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 5656. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This pathogenic mutation, also designated as 5884C>T, has been reported in two unrelated Korean individuals diagnosed with early onset breast cancer (Seong MW et al. Clin Genet. 2009 Aug;76(2):152-60). 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. -

Mar 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 11 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 has been reported in individuals affected with breast and ovarian cancer (PMID: 19656164, 22798144, 25863477, 30309222, 33471991; Leiden Open Variation Database DB-ID BRCA2_001603) and has been identified in 8 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. -

Breast and/or ovarian cancer Pathogenic:1

Mar 24, 2014

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:1

Dec 10, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.018
FATHMM_MKL	Benign	0.18	N
Vest4		0.96
GERP RS		3.8

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: rs80358790; hg19: chr13-32914148;