rs276174854

Positions:

• chr13-32339498-TTGTA-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.5146_5149del​(p.Tyr1716LysfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,583,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 0.655

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 13-32339498-TTGTA-T is Pathogenic according to our data. Variant chr13-32339498-TTGTA-T is described in ClinVar as [Pathogenic]. Clinvar id is 51779.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339498-TTGTA-T is described in Lovd as [Pathogenic]. Variant chr13-32339498-TTGTA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5146_5149del	p.Tyr1716LysfsTer8	frameshift_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5146_5149del	p.Tyr1716LysfsTer8	frameshift_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000441 AC: 1 AN: 226616 Hom.: 0 AF XY: 0.00000814 AC XY: 1 AN XY: 122864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000353

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431316 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 710288

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: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jan 26, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift deletion p.Y1716Kfs*8 in BRCA2 (NM_000059.4) has been previously reported in individuals affected with Breast and Ovarian cancer and is reported as a founder variant in Spanish populations (Infante et al, 2010; Llort et al, 2002; Jiménez et al, 2013). This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 8 residues until a stop codon is reached. The p.Y1716Kfs*8 variant is a loss of function variant in the gene BRCA2, which is intolerant of Loss of Function variants. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -
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, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, no assertion criteria provided	case-control	Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	May 24, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 22, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2019	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; Observed in individuals with breast and ovarian cancer, and is reported as a founder variant in Spanish populations (Llort 2002, Infante 2010, Gonzalez-Hormazabal 2011, de Juan Jimenez 2013, de Juan 2015); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as BRCA2 5374del4, 5373del4, c.5374_5377delTATG, or c.5373_5376delGTAT; This variant is associated with the following publications: (PMID: 28127413, 16261400, 29088781, 30103829, 19912264, 23479189, 11857748, 22460208, 12655567, 23929434, 20859677, 26026974, 25671134, 30720243, 31125277) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	This sequence change creates a premature translational stop signal (p.Tyr1716Lysfs*8) 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 present in population databases (rs763933639, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with male breast cancer and/or breast and/or ovarian cancer (PMID: 11857748, 16261400, 19912264, 20859677, 23199084, 23479189, 26026974). It is commonly reported in individuals of Spanish ancestry (PMID: 19912264, 23199084). This variant is also known as 5374delTATG, 5373delGTAT, c.5374_5377delTATG, c.5373_5376delGTAT. ClinVar contains an entry for this variant (Variation ID: 51779). 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	Feb 15, 2023	Variant summary: BRCA2 c.5146_5149delTATG (p.Tyr1716LysfsX8) 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 allele was found at a frequency of 4.4e-06 in 226616 control chromosomes. c.5146_5149delTATG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Tyr1716LysfsX8 variant was not identified in the literature. The p.Tyr1716LysfsX8 variant was identified in dbSNP (ID: rs763933639), Clinvitae database (as pathogenic by Invitae), ARUP Laboratories BRCA Mutations Database (as definitely pathogenic), the ClinVar database (as pathogenic by GeneDX, Ambry Genetics). The c.5146_5149delTATG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1716 and leads to a premature stop codon 8 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 10, 2023

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2023

The c.5146_5149delTATG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5146 to 5149, causing a translational frameshift with a predicted alternate stop codon (p.Y1716Kfs*8). This mutation has been observed in multiple breast and/or ovarian cancer families in the literature (Llort G et al. Hum. Mutat. 2002 Mar;19:307; de Juan Jiménez I et al. Fam. Cancer 2013 Dec;12:767-77). Haplotype analysis performed on 13 families with this mutation suggests that it originated in Spain from a common ancestor (Infante M et al. Clin. Genet. 2010 Jan;77:60-9), and one study identified this alteration in 2/312 Spanish male breast cancer patients (de Juan I et al. Fam. Cancer 2015 Dec;14:505-13). Of note, this alteration is also designated as 5373delGTAT, 5374del4, and 5146_5149del4 in published literature. 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. -

Computational scores

Source: dbNSFP v4.3

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: rs276174854; hg19: chr13-32913635;