13-32363182-T-G

Position:

• chr13-32363182-T-G

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.7980T>G​(p.Tyr2660*) 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:5
• Conservation: PhyloP100: 2.08

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 (HGNC:):

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 13-32363182-T-G is Pathogenic according to our data. Variant chr13-32363182-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 52459.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32363182-T-G is described in Lovd as [Pathogenic]. Variant chr13-32363182-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7980T>G	p.Tyr2660*	stop_gained	18/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7980T>G	p.Tyr2660*	stop_gained	18/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7611T>G	p.Tyr2537*	stop_gained	18/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*38T>G		non_coding_transcript_exon_variant	17/26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*38T>G		3_prime_UTR_variant	17/25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

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

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)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 17, 2021	This variant changes 1 nucleotide in exon 18 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer and at least one suspected hereditary breast and ovarian cancer family (PMID: 26833046, 32098980). 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	Mar 28, 2024	The p.Y2660* pathogenic mutation (also known as c.7980T>G), located in coding exon 17 of the BRCA2 gene, results from a T to G substitution at nucleotide position 7980. This changes the amino acid from a tyrosine to a stop codon within coding exon 17. This variant has been identified in individuals with a personal and/or family history suggestive of hereditary breast and ovarian cancer syndrome (Pritchard CC et al. N Engl J Med, 2016 Aug;375:443-53; Nielsen HR et al. Fam Cancer, 2016 Oct;15:507-12; Rumford M et al. Sci Rep, 2020 Feb;10:3390; Olafsdottir EJ et al. Br J Cancer, 2020 Nov;123:1608-1615; George SHL et al. JAMA Netw Open, 2021 Mar;4:e210307). 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. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Tyr2660* variant was identified in 1 of 59400 proband chromosomes (frequency: 0.00002) from individuals or families with breast or ovarian cancer (Rebbeck 2018). The variant was also identified in dbSNP (ID: rs397507949) as "With Pathogenic, Uncertain significance allele”, ClinVar (classified as pathogenic by Color, ENIGMA and CIMBA), LOVD 3.0 (4x as pathogenic), UMD-LSDB (1x as causal variant), and in ARUP Laboratories (definitely pathogenic), databases. The variant was not identified in COGR, Cosmic, BIC Database, or Zhejiang University, databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Tyr2660* variant leads to a premature stop codon at position 2660 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in breast or ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.89
GERP RS		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs397507949; hg19: chr13-32937319;