rs276174859

Variant names:

• chr13-32339964-TC-AG
• rs276174859
• NM_000059.4:c.5609_5610delTCinsAG

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.5609_5610delTCinsAG​(p.Phe1870*) variant causes a stop gained 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)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 0.153

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 13-32339964-TC-AG is Pathogenic according to our data. Variant chr13-32339964-TC-AG is described in ClinVar as [Pathogenic]. Clinvar id is 51890.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5609_5610delTCinsAG	p.Phe1870*	stop_gained		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5609_5610delTCinsAG	p.Phe1870*	stop_gained		5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5240_5241delTCinsAG	p.Phe1747*	stop_gained		1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5609_5610delTCinsAG		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 05, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -

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. -

Sep 14, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 17, 2015

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not provided Pathogenic:2

Mar 21, 2017

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 12, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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 5837_5838delTCinsAG; This variant is associated with the following publications: (PMID: 27003155, 21232165, 22923021, 28056804, 28324225, 16683254, 25447315, 16825431, 24156927, 22729890, 25583207, 23583677, 15689453, 28152038, 28288110, 24301060, 16115142, 15645491, 21719596, 30322717, 32341426, 33471991, 29446198, 36721989, 38219492, 18284688, 34680878, 12065746) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 29, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5609_5610delTCinsAG pathogenic mutation (also known as p.F1870*), located in coding exon 10 of the BRCA2 gene, results from an in-frame deletion of TC and insertion of AG at nucleotide positions 5609 to 5610. This changes the amino acid from a phenylalanine to a stop codon within coding exon 10. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date (Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Becker AA et al. Breast Cancer Res. Treat. 2012 Aug;135:167-75; Tea MK et al. Maturitas 2014 Jan;77:68-72; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238), and in an individual with Fanconi Anemia (Howlett NG et al. Science 2002 Jul;297:606-9). Of note, this alteration is also designated as 5837TC>AG 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. -

Jan 12, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a 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 (PMID: 18284688, 21232165, 22729890, 28324225, 34680878) and Fanconi anemia (PMID: 12065746). In a large breast cancer case-control study conducted by the Breast Cancer Association Consortium, this variant was reported in 2/60466 cases and 0/53461 controls (p-value=0.502) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001645). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Apr 21, 2023

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.5609_5610delinsAG (p.Phe1870X) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 247384 control chromosomes. c.5609_5610delinsAG has been reported in the literature in individuals and families affected with Hereditary Breast And Ovarian Cancer Syndrome (Becker_2012, Novakovic_2012, Stegel_2011, Tea_2014) and observed in a compound heterozygous Fanconi Anemia patient (Howlett_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 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. -

May 06, 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.Phe1870*) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer and Fanconi anemia (PMID: 12065746, 21232165, 22729890, 22923021, 24156927). This variant is also known as 5837 TC to AG. ClinVar contains an entry for this variant (Variation ID: 51890). For these reasons, this variant has been classified as Pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BAP1-related tumor predisposition syndrome Pathogenic:1

Jun 29, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5609_5610delTCinsAG pathogenic mutation (also known as p.F1870* and 5837TC>AG), located in coding exon 10 of the BRCA2 gene, results from the deletion and insertion of 2 nucleotides at positions 5609 and 5610. This changes the amino acid at codon 1870 from a phenylalanine to a stop codon. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date (Stegel et al. BMC Med Genet. 2011 Jan 14;12:9; Becker et al. Breast Cancer Res Treat. 2012 Aug;135(1):167-75; Tea MK et al. Maturitas. 2014 Jan;77(1):68-72) and in an individual with Fanconi Anemia (Howlett et al. Science. 2002 Jul 26;297(5581):606-9). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Fanconi anemia complementation group D1 Pathogenic:1

Jul 26, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Familial cancer of breast Pathogenic:1

Jun 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: rs276174859; hg19: chr13-32914101;