rs80359451

Positions:

• chr13-32338824-TACTG-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.4471_4474del​(p.Leu1491LysfsTer12) 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 0.658

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 13-32338824-TACTG-T is Pathogenic according to our data. Variant chr13-32338824-TACTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 51652.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338824-TACTG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.4471_4474del	p.Leu1491LysfsTer12	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.4471_4474del	p.Leu1491LysfsTer12	frameshift_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250468 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135584

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

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 Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461502 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727054

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 14, 2023	The BRCA2 c.4471_4474del (p.Leu1491LysfsTer12) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. Across a selection of the literature this variant has been identified in at least five individuals with a breast cancer phenotype (PMIDs: 24013928; 34645131; 3265831; 35710434). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence the c.4471_4474del (p.Leu1491LysfsTer12) variant is classified as likely pathogenic for hereditary breast and ovarian cancer. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
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	Sharing Clinical Reports Project (SCRP)	Apr 06, 2009	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 01, 2022	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/250468 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 24013928 (2014), 30350268 (2018), 32658311 (2021), and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2022	Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Pal et al., 2014; Park et al., 2018; Ryu et al., 2019; Akcay et al., 2020); 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; 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 4699_4702delCTGA; This variant is associated with the following publications: (PMID: 24013928, 26287763, 29128982, 29673794, 28918466, 30720243, 30350268, 30787465, 32658311, 31875949) -
Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 08, 2022	DNA sequence analysis of the BRCA2 gene demonstrated a four base pair deletion in exon 11, c.4471_4474del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 12 amino acids downstream of the change, p.Leu1491Lysfs*12. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA2 protein with potentially abnormal function. This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.00040% (dbSNP rs1442953012). This sequence change has previously been described in individuals with breast cancer and colorectal cancer (PMID: 24013928, 30350268, 31875949, 32658311). Based on these collective evidences, this sequence change is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 10, 2021	The c.4471_4474delCTGA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at positions 4471 to 4474, causing a translational frameshift with a predicted alternate stop codon (p.L1491Kfs*12). This alteration, also designated as 4699del4 in the literature, has been identified in several cohorts of breast cancer patients (Pal T et al. J. Community Genet. 2014 Apr; 5(2):157-65; Ryu JM et al. Breast Cancer Res Treat. 2019 Jan;173:385-395; Akcay IM et al. Int J Cancer. 2021 01;148:285-295). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 14, 2022	This variant deletes 4 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 1 individual affected with pancreatic cancer (PMID: 35008403), 1 individual affected with ovarian cancer (PMID: 34657357), 5 individuals affected with breast cancer (PMID: 24013928, 30350268, 33471991; Leiden Open Variation Database DB-ID BRCA2_004644, 34645131) and 2 individuals affected with colorectal cancer (PMID: 31875949). This variant has been identified in 1/250468 chromosomes 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	Jan 02, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 11, 2024	Variant summary: BRCA2 c.4471_4474delCTGA (p.Leu1491LysfsX12) 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. The variant allele was found at a frequency of 4e-06 in 250468 control chromosomes. c.4471_4474delCTGA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Pal_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 24013928). ClinVar contains an entry for this variant (Variation ID: 51652). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change creates a premature translational stop signal (p.Leu1491Lysfs*12) 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 (rs80359451, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 24013928). This variant is also known as 4699del4. ClinVar contains an entry for this variant (Variation ID: 51652). For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 03, 2022

- -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 08, 2021

Invasive Ductal Carcinoma Estrogen Receptor: Negative Progesterone Receptor: Negative HER2 Receptor: Negative -

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: rs80359451; hg19: chr13-32912961;