rs80359154

Positions:

• chr13-32379814-C-A
• chr13-32379814-C-G
• chr13-32379814-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.9018C>A​(p.Tyr3006Ter) 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:8
• Conservation: PhyloP100: 0.154

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 13-32379814-C-A is Pathogenic according to our data. Variant chr13-32379814-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 52728.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379814-C-A is described in Lovd as [Pathogenic]. Variant chr13-32379814-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9018C>A	p.Tyr3006Ter	stop_gained	23/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9018C>A	p.Tyr3006Ter	stop_gained	23/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 21, 2022	This variant changes 1 nucleotide in exon 23 of the BRCA2 gene, creating a premature translation stop signal. This variant is also known as 9246C>A in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in more than 10 individuals affected with breast, ovarian, or pancreatic cancer (PMID: 18176857, 26026974, 29020732, 29673794, 29884136, 32073954, 33471991). This variant has also been reported in several suspected HBOC families, including 19 families among CIMBA participants (PMID: 12955716, 20033483, 29446198). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 01, 2024	The p.Y3006* pathogenic mutation (also known as c.9018C>A), located in coding exon 22 of the BRCA2 gene, results from a C to A substitution at nucleotide position 9018. This changes the amino acid from a tyrosine to a stop codon within coding exon 22. This mutation, also designated as 9246C>A, has been reported in two unrelated Spanish families with breast and ovarian cancer histories (Díez O et al. Hum Mutat, 2003 Oct;22:301-12). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2017	Variant summary: The BRCA2 c.9018C>A (p.Tyr3006X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.9196C>T, p.Gln3066X; c.9235delG, p.Val3079fsX4; c.9253dupA, p.Thr3085fsX26). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121016 control chromosomes and has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 08, 2021	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52728). This variant is also known as c.9246C>A. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12955716, 18176857, 20033483, 26026974, 29020732, 29446198, 29884136). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr3006*) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Uncertain	0.98
Eigen	Benign	0.049
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A
Vest4		0.86
GERP RS		-1.2

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: rs80359154; hg19: chr13-32953951; COSMIC: COSV66457732; COSMIC: COSV66457732;