rs80359593

Variant names:

• chr13-32340799-TATTAA-T
• rs80359593
• NM_000059.4:c.6446_6450delTTAAA

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.6446_6450delTTAAA​(p.Ile2149SerfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,439,916 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: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 1.01

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 13-32340799-TATTAA-T is Pathogenic according to our data. Variant chr13-32340799-TATTAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 52102.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340799-TATTAA-T is described in Lovd as [Pathogenic]. Variant chr13-32340799-TATTAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6446_6450delTTAAA	p.Ile2149SerfsTer25	frameshift_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6446_6450delTTAAA	p.Ile2149SerfsTer25	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6077_6081delTTAAA	p.Ile2026SerfsTer25	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6446_6450delTTAAA		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1439916 Hom.: 0 AF XY: 0.00000140 AC XY: 1 AN XY: 715440

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

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

Dec 23, 2003

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 19, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ile2149Serfs*25) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15131399, 20858050). ClinVar contains an entry for this variant (Variation ID: 52102). For these reasons, this variant has been classified as Pathogenic. -

Mar 14, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.6446_6450delTTAAA (p.Ile2149SerfsX25) 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 was absent in 230326 control chromosomes. c.6446_6450delTTAAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Coulet_2010, Dworkin_2009, Nakamura_2013, Lubinski_2004, Kanke_2018, Kwong_2015). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories, one expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Aug 05, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.6446_6450delTTAAA; p.Ile2149fs variant (rs80359593), also known as 6674del5, is reported in the literature in multiple individuals affected with hereditary breast and ovarian cancers (Dworkin 2009, Kanke 2017, Kwong 2016, Lubinski 2004, Nakamura 2015). This variant is reported in ClinVar (Variation ID: 52102), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 5 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several other downstream truncating variants have been reported in individuals with breast and ovarian cancers and are considered pathogenic Kwong 2016, Lubinski 2004, Nakamura 2015). Based on available information, this variant is considered to be pathogenic. References: Dworkin AM et al. Methylation not a frequent "second hit" in tumors with germline BRCA mutations. Fam Cancer. 2009;8(4):339-46. Kanke Y et al. Gene aberration profile of tumors of adolescent and young adult females. Oncotarget. 2017 Dec 29;9(5):6228-6237. Kwong A et al. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries. J Med Genet. 2016 Jan;53(1):15-23. Lubinski J et al. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3(1):1-10. Nakamura S et al. Prevalence and differentiation of hereditary breast and ovarian cancers in Japan. Breast Cancer. 2015 Sep;22(5):462-8. -

Oct 01, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 BRCA2-related cancers (Lubinksi 2004, Dworkin 2009, Foley 2015, Nakamura 2015, Kanke 2018, Momozawa 2018); Not observed 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 6445_6449del5, 6674del5, or 6674_6678delTTAAA; This variant is associated with the following publications: (PMID: 31214711, 29176636, 19340607, 20858050, 24249303, 26023681, 26187060, 29464067, 30287823, 15131399) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 15, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 5 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 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. -

Jul 11, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6446_6450delTTAAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 6446 to 6450, causing a translational frameshift with a predicted alternate stop codon (p.I2149Sfs*25). This pathogenic mutation has been reported in individuals with HBOC-related cancers (Lubinski J et al. Fam. Cancer. 2004;3(1):1-10; Dworkin AM et al. Fam. Cancer 2009 Apr;8(4):339-46; Foley SB et al. EBioMedicine 2015 Jan;2(1):74-81), and in Japanese breast cancer cohorts (Nakamura S et al. Breast Cancer 2015 Sep;22(5):462-8; Kwong A et al. J. Med. Genet. 2016 Jan;53(1):15-23; Momozawa Y et al. Nat. Commun. 2018 10;9(1):4083). Of note, this alteration is also designated as 6674del5 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. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

Mar 13, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:1

Jan 21, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs80359593; hg19: chr13-32914936;