13-32326143-TAAGTC-T

Position:

• chr13-32326143-TAAGTC-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.470_474delAGTCA​(p.Lys157fs) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,456,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. KS157K?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 6.08

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 13-32326143-TAAGTC-T is Pathogenic according to our data. Variant chr13-32326143-TAAGTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 51701.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32326143-TAAGTC-T is described in Lovd as [Pathogenic]. Variant chr13-32326143-TAAGTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.470_474delAGTCA	p.Lys157fs	frameshift_variant, splice_region_variant	5/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.470_474delAGTCA	p.Lys157fs	frameshift_variant, splice_region_variant	5/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.101_105delAGTCA	p.Lys34fs	frameshift_variant, splice_region_variant	5/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.470_474delAGTCA		splice_region_variant, non_coding_transcript_exon_variant	4/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456774 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 724916

Gnomad4 AFR exome AF: 0.00

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

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:5

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, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 19, 2006	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 05, 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 breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2022	For these reasons, this variant has been classified as Pathogenic. Studies have shown this premature translational stop signal is associated with skipping of exon 5, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 20215541, 27060066). ClinVar contains an entry for this variant (Variation ID: 51701). This variant is also known as 698del5, Stop 180, c.469_473del. This premature translational stop signal has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 17851763, 27767231, 28294317, 28724667, 29487695). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys157Serfs*24) 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). -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2022	This variant deletes 5 nucleotides in exon 5 of the BRCA2 protein, 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 11 individuals affected with breast or ovarian cancer (PMID: 17851763, 28294317, 29487695, 31174498, doi:10.1515/tjb-2019-0424) and has been identified in 5 families among the CIMBA participants (PMID: 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	Nov 04, 2024	The c.470_474delAGTCA pathogenic mutation, located in coding exon 4 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 470 to 474, causing a translational frameshift with a predicted alternate stop codon (p.K157Sfs*24). In addition to causing premature protein truncation, functional splicing analysis demonstrates that this alteration also results in exon 5 skipping via disruption of the exonic splicing enhancer (Sanz DJ et al. Clin. Cancer Res. 2010; 16:1957-67). This alteration was previously reported in one individual with breast cancer at age 32 from a Chinese cohort of 489 breast cancer patients with a diagnosis under the age of 35 or a family history of breast and/or ovarian cancer ( Li WF et al. Breast Cancer Res. Treat. 2008; 110:99-109). 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, criteria provided, single submitter

clinical testing

GeneDx

Mar 30, 2022

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease, while also shown to result in aberrant splicing resulting in multiple transcripts including deletion exon 5 (Sanz 2010, Stauffer 2020); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Li 2008, Cao 2016, Weren 2016, Sun 2017); Published functional studies demonstrate a damaging effect: reduced cell viability and hypersensitivity to DNA damaging agents (Stauffer 2020); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 698_702del or 469_473del; This variant is associated with the following publications: (PMID: 30720863, 28176296, 30702160, 31174498, 27060066, 29487695, 28294317, 26295337, 33563323, 32926049, 26852015, 32623769, 30883759, 31825140, 17851763, 20215541, 22632462, 32393813, 28724667, 27767231) -

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: rs80359463; hg19: chr13-32900280;