chr13-32337542-C-T

Position:

• chr13-32337542-C-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.3187C>T​(p.Gln1063*) 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: 32)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 0.107

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]

BRCA2 (HGNC:):

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 13-32337542-C-T is Pathogenic according to our data. Variant chr13-32337542-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 228324.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337542-C-T is described in Lovd as [Pathogenic]. Variant chr13-32337542-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.3187C>T	p.Gln1063*	stop_gained	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.3187C>T	p.Gln1063*	stop_gained	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.2818C>T	p.Gln940*	stop_gained	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.3187C>T		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5

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, criteria provided, single submitter	clinical testing	Bioinformatics dept., Datar Cancer Genetics Limited, India	Jul 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Endocrinology Laboratory, Christian Medical College	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jul 22, 2023	The observed stop gained c.3187C>T p.Gln1063Ter variant in BRCA2 gene has been reported previously in multiple individuals affected with hereditary breast and ovarian cancer HBOC syndrome Kwong et al., 2016; Mannan et al., 2016 Rebbeck et al., 2018. This variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic multiple submissions. Computational evidence MutationTaster - Disease causing predicts damaging effect on protein structure and function for this variant. The reference amino acid of p.Gln1063Ter in BRCA2 is predicted as conserved by PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in BRCA2 gene have been previously reported to be disease causing Borg et al., 2010. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Oct 18, 2016	Variant allele predicted to encode a truncated non-functional protein. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 25, 2021	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 25863477, 26187060, 26911350). 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	Sep 23, 2022	The p.Q1063* pathogenic mutation (also known as c.3187C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 3187. This changes the amino acid from a glutamine to a stop codon within coding exon 10. 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 13, 2016	Variant summary: The BRCA2 c.3187C>T (p.Gln1063X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g. c.6124C>T/p.Gln2042X, c.6997_6998delGT/p.Val2333fsX6, ). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in multiple HBOC patients and is absent in 120248 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 18, 2018	The p.Gln1063X variant in BRCA2 has been reported in at least 4 individuals with BRCA2-associated cancers (Kang 2015, Kwong 2016, Mannan 2016). This variant was absent from large population studies. This nonsense variant leads to a prematur e termination codon at position 1063, which is predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 function is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). This variant was clas sified as PATHOGENIC on Oct 18, 2016 by the ClinGen-approved Enigma expert panel (ClinVar SCV000324138.1). In summary, this variant is pathogenic for HBOC in an autosomal dominant manner based upon its predicated impact to the protein and p resence in affected individuals. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Suppo rting. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 21, 2023	This sequence change creates a premature translational stop signal (p.Gln1063*) 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 clinical features of hereditary breast and ovarian cancer (HBOC) syndrome (PMID: 26187060, 26911350, 29446198). ClinVar contains an entry for this variant (Variation ID: 228324). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2022	Nonsense 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 association with breast and/or ovarian cancer (Kang 2015, Mannan 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (gnomAD); Also known as 3415C>T; This variant is associated with the following publications: (PMID: 26911350, 25863477, 26187060, 28008009, 29446198, 31447099) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 12, 2023	The BRCA2 c.3187C>T (p.Gln1063*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals and families affected with breast and/or ovarian cancer (PMIDs: 25863477 (2015), 26187060 (2015), 26911350 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	31
DANN	Uncertain	0.98
Eigen	Benign	0.033
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.087	N
Vest4		0.89
GERP RS		-0.36

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: rs876657678; hg19: chr13-32911679; COSMIC: COSV66451422; COSMIC: COSV66451422;