rs80359148

chr13-32379765-G-Achr13-32379765-G-Cchr13-32379765-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.8969G>A(p.Trp2990Ter) variant causes a stop gained change involving the alteration of a 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:9
• Conservation: PhyloP100: 9.02

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 13-32379765-G-A is Pathogenic according to our data. Variant chr13-32379765-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 126195.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379765-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8969G>A	p.Trp2990Ter	stop_gained	23/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8969G>A	p.Trp2990Ter	stop_gained	23/27	5	NM_000059.4	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, 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)	Jan 21, 2010	- -
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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	Predicted to result in protein truncation or nonsense mediated decay, either by premature stop or splice defect, in a gene for which loss-of-function is a known mechanism of disease (Acedo 2012); 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; Observed in individuals with BRCA2-related cancers (Borg 2010, Ellingson 2015, Pal 2015, Dong 2018, Ryu 2019); This variant is associated with the following publications: (PMID: 20104584, 30350268, 32623769, 22632462, 17899372, 26296701, 26287763, 23893897, 30039884, 29202330, 32926152) -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 01, 2023	This sequence change creates a premature translational stop signal (p.Trp2990*) 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 breast cancer (PMID: 20104584, 26287763, 26296701). This variant is also known as 9197G>A. ClinVar contains an entry for this variant (Variation ID: 126195). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2020	Variant summary: BRCA2 c.8969G>A (p.Trp2990X) 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. The variant was absent in 250750 control chromosomes. c.8969G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and as a somatic occurrence in at-least one patient with triple negative breast cancer (TNBC) (example, Borg_2010, Ellingson_2015, Pal_2015, Pop_2018, Ryu_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 14, 2021

The p.W2990* pathogenic mutation (also known as c.8969G>A), located in coding exon 22 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8969. This changes the amino acid from a tryptophan to a stop codon within coding exon 22. This pathogenic mutation has been reported in multiple women with early-onset and/or familial breast cancer (Borg A et al. Hum. Mutat. 2010 Mar; 31(3):E1200-40; Ellingson MS et al. Breast Cancer Res. Treat. 2015 Sep;153(2):435-43; Pal T et al. Cancer 2015 Dec;121(23):4173-80; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Yadav S et al. J Clin Oncol, 2020 05;38:1409-1418; Dong L et al. Hum Mutat, 2018 10;39:1442-1455). In addition, studies have shown that c.8969G>A is located in a conserved exonic splice enhancing region and is predicted to enhance cryptic splicing (Pettigrew CA et al. Breast Cancer Res. Treat. 2008 Jul; 110(2):227-34; Acedo A et al. Breast Cancer Res. 2012; 14(3):R87). 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 13, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	50
Dann	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A
Vest4		0.83
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.33		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80359148; hg19: chr13-32953902;