rs80359205

Positions:

• chr13-32394749-G-A
• chr13-32394749-G-C
• chr13-32394749-G-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.9317G>A​(p.Trp3106Ter) variant causes a stop gained change. 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:9
• Conservation: PhyloP100: 6.50

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 13-32394749-G-A is Pathogenic according to our data. Variant chr13-32394749-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 52814.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32394749-G-A is described in Lovd as [Pathogenic]. Variant chr13-32394749-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9317G>A	p.Trp3106Ter	stop_gained	25/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9317G>A	p.Trp3106Ter	stop_gained	25/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

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

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)	Dec 23, 2003	- -
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. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This sequence change creates a premature translational stop signal at codon 3106 of the BRCA2 protein. It is expected to result in an absent or disrupted protein product. Truncating mutations in BRCA2 are known to be pathogenic. This variant is listed in the mutation database ClinVar (Variation ID: 52814/). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 27, 2024	- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

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	Mar 12, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52814). This premature translational stop signal has been observed in individual(s) with with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 27257965, 27478808, 28724667, 30702160). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp3106*) 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). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2019

The p.W3106* pathogenic mutation (also known as c.9317G>A), located in coding exon 24 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9317. This changes the amino acid from a tryptophan to a stop codon within coding exon 24. This alteration was reported in an Iranian male diagnosed with breast cancer (Zorrieh Zahra A et al. Int J Mol Cell Med. 2016 May;5:114-22), a male diagnosed with Gleason 7 prostate cancer (Ibrahim M et al. BMC Cancer 2018 02;18:179), and in multiple cohorts of Chinese breast cancer patients (Zhang J et al. Breast Cancer Res. Treat. 2016 08;158:455-62; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Liang Y et al. Med. Sci. Monit. 2018 Apr;24:2465-2475; Bhaskaran SP et al. Int. J. Cancer 2019 Jan). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). 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. -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Sep 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	48
DANN	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.97
GERP RS		5.9

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: rs80359205; hg19: chr13-32968886;