chr13-32332739-C-T

Position:

• chr13-32332739-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.1261C>T​(p.Gln421*) 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:10 O:1
• Conservation: PhyloP100: 1.09

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 13-32332739-C-T is Pathogenic according to our data. Variant chr13-32332739-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 51092.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332739-C-T is described in Lovd as [Pathogenic]. Variant chr13-32332739-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.1261C>T	p.Gln421*	stop_gained	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1261C>T	p.Gln421*	stop_gained	10/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.892C>T	p.Gln298*	stop_gained	10/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.1261C>T		non_coding_transcript_exon_variant	9/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 15, 2018	Variant summary: BRCA2 c.1261C>T (p.Gln421X) 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 (eg. c.1265delA (p.Asn422fsX8), c.1310_1313delAAGA (p.Lys437fsX22), and c.1456C>T (p.Gln486X)). The variant was absent in 240472 control chromosomes (gnomAD). The variant, c.1261C>T, has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Kwong_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite 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	Labcorp Genetics (formerly Invitae), Labcorp	May 25, 2021	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 19353265, 29446198). ClinVar contains an entry for this variant (Variation ID: 51092). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln421*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. -

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3 Other:1

not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 15, 2023	The c.1261C>T (p.Gln421*) variant in the BRCA2 gene is located on the exon 10 and introduces a premature translation termination codon (p.Gln421*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast/ovarian/prostate cancer (PMID: 31209999, 19353265, 35464868, 22970155, 31214711, 30287823). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 51092) and reviewed by the expert panel. This variant is absent in the general population database (gnomAD). Therefore, the c.1261C>T (p.Gln421*) variant of BRCA2 has been 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, 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. -

Malignant tumor of urinary bladder Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Urology, Hospital Clinic de Barcelona

-

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 14, 2022

The p.Q421* pathogenic mutation (also known as c.1261C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1261. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been reported in multiple high-risk breast and/or ovarian cancer cohorts (Kwong et al. Breast Cancer Res Treat. 2009 Oct;117(3):683-6; Kwong et al. PLoS One. 2012;7(9):e43994; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Huang KL et al. Cell, 2018 04;173:355-370.e14). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.35	N
Vest4		0.92
GERP RS		5.1

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: rs80358419; hg19: chr13-32906876;