Variant rs80359421 details in Genebe, Genetics Data Aggregator

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 links:

ACMG classification

Classification made for transcript

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 13-32338391-ACT-A is Pathogenic according to our data. Variant chr13-32338391-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 51584.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338391-ACT-A is described in Lovd as [Pathogenic]. Variant chr13-32338391-ACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.4037_4038del	p.Thr1346SerfsTer5	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 linkuse as main transcript	c.4037_4038del	p.Thr1346SerfsTer5	frameshift_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

LINK: link

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)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 03, 2016	- -
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	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 01, 2013	- -
Likely pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_000059.4:c.4037_4038del (chr13:32338391) in BRCA2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. -
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. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 22, 2021	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 30078507 (2018), 28993434 (2018), 26187060 (2015), 18627636 (2008), 17591843 (2007), 11920621 (2002), 10644434 (1999)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 22, 2022	PP5, PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2024	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 a personal or family history consistent with pathogenic variants in this gene and has been described as a Filipino founder variant (PMID: 10615237, 10644434, 11920621, 15131399, 18627636); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4265delCT and 4265_4266delCT; This variant is associated with the following publications: (PMID: 30350268, 30078507, 10644434, 18627636, 11920621, 26187060, 17591843, 12442265, 23364291, 10615237, 15131399, 28993434, 24578176, 34645131, 37937776, 33558524, 33461583, 29922827, 36385461, 32341426, 37310942) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jan 03, 2023	- -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2020	The p.Thr1346SerfsX5 variant in BRCA2 has been identified in at least 11 individuals with BRCA2-related cancers (Johannsson 1999, De Leon Matsuda 2002,Lubinski 2014, Thirthagiri 2008, Li 2018, Wen 2018, Ryu 2019). This variant has been identified in 1/65954 chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1346 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). This variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282386.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Thr1346Serfs*5) 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 BRCA2-related conditions (PMID: 10644434, 11920621, 28993434, 30078507, 30350268, 32341426, 33558524). This variant is also known as 4265delCT. ClinVar contains an entry for this variant (Variation ID: 51584). 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	Jul 09, 2024	Variant summary: BRCA2 c.4037_4038delCT (p.Thr1346SerfsX5), also known as 4265delCT, 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.4037_4038delCT has been reported in the literature in the heterozygous state in multiple individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome (example, De Leon Matsuda_2002, Thirthagiri_2008, Li_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11920621, 30078507, 18627636). ClinVar contains an entry for this variant (Variation ID: 51584). Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial cancer of breast

Pathogenic:2

Pathogenic, no assertion criteria provided	research	Center of Medical Genetics and Primary Health Care	Apr 08, 2020	ACMG Guidelines 2015 criteria The BRCA2 variant p.Thr1346Serfs is a known pathogenic variant in exon 11 in a non-functional domain just before the BRCA2_REPEAT (F1421-1454P aa) domain, which, with other 39 aa repeats participates in RAD51 binding (a key protein in DNA recombinational repair) and confers resistance to methyl methanesulphonate treatment. This frameshift variant disrupts the function of the downstream domains which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This variant is in a mutation hotspot region of 21 pathogenic variants (source, ClinVar) (PM1 Pathogenic Moderate). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282386.1) (PP5 Pathogenic Supporting). In our study this variant was found in a 53-year-old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 15, 2023	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 15, 2022	The c.4037_4038delCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 4037 to 4038, causing a translational frameshift with a predicted alternate stop codon (p.T1346Sfs*5). This mutation has been reported in multiple individuals with hereditary breast and ovarian cancer (HBOC) syndrome, and is commonly described as a founder mutation in the Filipino and Malay populations (Wagner T et al. Genomics 1999 Dec;62(3):369-76; De Leon Matsuda ML et al Int. J. Cancer 2002 Apr;98(4):596-603; Thirthagiri E et al Breast Cancer Res. 2008 Jul;10(4):R59; Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; De Talhouet S et al. Sci Rep, 2020 04;10:7073; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). Of note, this alteration is also designated as 4265delCT 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 27, 2023	This variant deletes 2 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 at least eight individuals affected with breast and/or ovarian cancer and in additional suspected hereditary breast and ovarian cancer families (PMID: 10615237, 10644434, 11920621, 15131399, 18627636, 28993434, 30078507, 30350268, 32341426, 33558524). Haplotype analysis among Filipino carriers affected with breast cancer suggests that this variant may be a founder mutation in this population (PMID: 11920621). 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. -

Computational scores

Source: dbNSFP v4.3

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Splicing

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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

Below is the list of publications found by LitVar. It may be empty.

rs80359421

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation