rs397507858

chr13-32340801-T-TTA

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.6447_6448dup(p.Lys2150IlefsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. I2149I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: -0.698

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 13-32340801-T-TTA is Pathogenic according to our data. Variant chr13-32340801-T-TTA is described in ClinVar as [Pathogenic]. Clinvar id is 52104.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.6447_6448dup	p.Lys2150IlefsTer19	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6447_6448dup	p.Lys2150IlefsTer19	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3

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	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 06, 2015	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 07, 2022	This variant inserts 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer and in high-risk breast and ovarian cancer families (PMID: 11802209, 21204799, 22072316, 24152768, 27393621, 28943953). 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	curation	Sema4, Sema4	Dec 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2021	The c.6447_6448dupTA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of TA at nucleotide position 6447, causing a translational frameshift with a predicted alternate stop codon (p.K2150Ifs*19). This alteration has been detected in individuals from many breast/ovarian cancer cohorts (Meindl A et al. Int J Cancer, 2002 Feb;97:472-80); (Concolino P et al. Int J Mol Sci, 2019 Jul;20:); (Zhang J et al. Breast Cancer Res Treat, 2016 08;158:455-62); (Oosthuizen J et al. Front Oncol, 2020 Feb;10:619469); (De Talhouet S et al. Sci Rep, 2020 04;10:7073). Of note, this alteration is also designated as "6676dupTA" and "6676insTA" in published literature. 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:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2015	This duplication of 2 nucleotides in BRCA2 is denoted c.6447_6448dupTA at the cDNA level and p.Lys2150IlefsX19 (K2150IfsX19) at the protein level. This duplication is also known as BRCA2 6675_6676dupTA or 6676insTA using alternate nomenclature. The normal sequence, with the bases that are duplicated in braces, is CTAT[TA]AAGT. The duplication causes a frameshift, which changes a Lysine to an Isoleucine at codon 2150, and creates a premature stop codon at position 19 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.6447_6448dupTA has been identified in several individuals with a personal/family history of early-onset breast cancer, male breast cancer, and/or ovarian cancer (Meindl 2002, van der Merwe 2012, Pilato 2014). we consider this variant to be pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 03, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52104). This variant is also known as 6676insTA. This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 11802209, 21204799, 22072316, 24152768, 27393621, 28943953). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys2150Ilefs*19) 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	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397507858; hg19: chr13-32914938;