dbSNP rs80358810: BRCA2:p.Trp194* (chr13-32326564-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000059.4(BRCA2):c.582G>A(p.Trp194*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,674 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 (★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 6.72

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 13-32326564-G-A is Pathogenic according to our data. Variant chr13-32326564-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38000.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32326564-G-A is described in Lovd as [Pathogenic]. Variant chr13-32326564-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.582G>A	p.Trp194*	stop_gained	Exon 7 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.582G>A	p.Trp194*	stop_gained	Exon 7 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.213G>A	p.Trp71*	stop_gained	Exon 7 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.582G>A		non_coding_transcript_exon_variant	Exon 6 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:4

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. -

Nov 13, 1997

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

- -

Apr 20, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Jul 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 38000). This premature translational stop signal has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 26577449, 27767231, 28664506, 29446198). This variant has been reported in individual(s) with autosomal recessive Fanconi anemia (PMID: 28185119); however, the role of the variant in this condition is currently unclear. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp194*) 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). For these reasons, this variant has been classified as Pathogenic. -

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inherited breast cancer and ovarian cancer

Pathogenic:1

Nov 19, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1,PM5_Strong -

BRCA2-related cancer predisposition

Pathogenic:1

Dec 11, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of urinary bladder

Pathogenic:1

Laboratory of Urology, Hospital Clinic de Barcelona

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Oct 31, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W194* pathogenic mutation (also known as c.582G>A), located in coding exon 6 of the BRCA2 gene, results from a G to A substitution at nucleotide position 582. This changes the amino acid from a tryptophan to a stop codon within coding exon 6. This alteration has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Couch FJ et al. Nat. Genet., 1996 May;13:123-5; Francies FZ et al. BMC Cancer, 2015 Nov;15:912; Yang XR et al. Breast Cancer Res Treat, 2017 Oct;165:687-697; Oosthuizen J et al. Front Oncol, 2020 Feb;10:619469). This variant was also reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439) and in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Additionally, this alteration has been confirmed to be in trans with another pathogenic BRCA2 mutation in an individual diagnosed with Fanconi anemia (Feben C et al. Fam Cancer, 2017 07;16:441-446). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

0.61

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.97

Vest4

0.76

GERP RS

5.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over