13-32355033-A-T

Position:

• chr13-32355033-A-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.7180A>T​(p.Arg2394Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R2394R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 1.42

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 13-32355033-A-T is Pathogenic according to our data. Variant chr13-32355033-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 52279.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32355033-A-T is described in Lovd as [Pathogenic]. Variant chr13-32355033-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7180A>T	p.Arg2394Ter	stop_gained	14/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7180A>T	p.Arg2394Ter	stop_gained	14/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74382

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

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

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, criteria provided, single submitter	clinical testing	Counsyl	Sep 06, 2016	- -
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)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 28, 2010	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 30, 2017	Variant summary: The BRCA2 c.7180A>T (p.Arg2394X) 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. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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	Invitae	Dec 04, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52279). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer syndrome and breast and/or ovarian cancer, and pancreatic cancer (PMID: 15340362, 24065114, 25136594, 25366421, 28454591). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg2394*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	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 individuals with a personal or family history consistent with pathogenic variants in this gene (Marroni 2004, Ratajska 2015, Fernandes 2016); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 7408A>T; This variant is associated with the following publications: (PMID: 26689913, 29625052, 30736435, 29446198, 17224268, 27836010, 29907814, 25366421, 27741520, 21990299, 24131973, 15340362, 25525159) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	BRCA2: PVS1, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 28, 2018	The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 19, 2021	The p.R2394* pathogenic mutation (also known as c.7180A>T), located in coding exon 13 of the BRCA2 gene, results from an A to T substitution at nucleotide position 7180. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Marroni F et al. Eur J Hum Genet, 2004 Nov;12:899-906; Manoukian S et al. Eur J Cancer, 2007 Feb;43:601-6; Bellacosa A et al. Cancer Prev Res (Phila), 2010 Jan;3:48-61; Yang D et al. JAMA, 2011 Oct;306:1557-65; Ratajska M et al. J Appl Genet, 2015 May;56:193-8; Rebbeck TR et al. Breast Cancer Res, 2016 11;18:112; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481; Hoyer J et al. BMC Cancer, 2018 Sep;18:926; Concolino P et al. Int J Mol Sci, 2019 Jul;20; Santonocito C et al. Cancers (Basel), 2020 May;12). This mutation has also been detected in patients with pancreatic cancer (Humphris JL et al. Gastroenterology, 2017 01;152:68-74.e2; Johns AL et al. Genome Med, 2017 04;9:41). Of note, this alteration is also designated as 7408A>T in published literature. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2022	This variant changes 1 nucleotide in exon 14 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 at least 5 individuals affected with breast and ovarian cancer (PMID: 24131973, 25136594, 25366421, 27836010) and an individual affected with pancreatic cancer (PMID: 34200245). 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Benign	-0.089
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.37	N
MutationTaster	Benign	1.0	A;A
Vest4		0.84
GERP RS		3.1

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: rs80358946; hg19: chr13-32929170;