rs80359395

Positions:

• chr13-32338034-CTG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.3680_3681del​(p.Leu1227GlnfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000186 in 1,611,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L1227L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:22
• Conservation: PhyloP100: 5.94

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32338034-CTG-C is Pathogenic according to our data. Variant chr13-32338034-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 51504.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338034-CTG-C is described in Lovd as [Pathogenic]. Variant chr13-32338034-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.3680_3681del	p.Leu1227GlnfsTer5	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.3680_3681del	p.Leu1227GlnfsTer5	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1459732 Hom.: 0 AF XY: 0.0000179 AC XY: 13 AN XY: 725926

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

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

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 20, 2021	BRCA2:c.3680_3681delTG is classified as PATHOGENIC (ENIGMA criteria 2017) BRCA2:c.3680_3681delTG is a deletion of two consecutive nucleotides in exon 11 that predicts a frame-shift of the mature mRNA with consequent premature termination of protein synthesis at codon 5 of the frame shift, or 1232 BRCA2:p.(Leu1227GlnfsTer5) using NP_000050.2. BRCA2 variants of this type are widely accepted to be pathogenic (Tayoun et al 2018, PMID: 30192042). This variant has been reviewed by the ENIGMA expert review panel: ENIGMA determine BRCA2:c.3680_3681delTG as consistent with an IARC Class 5 variant equivalent to ACMG classification of Pathogenic. This variant has been reported in the scientific literature in individuals with breast cancer (Wen et al., 2018 PMID:28993434), invasive lobular breast cancer (Petridis et al., 2019 PMID:31263054), and ovarian cancer (Cotrim et al., 2019 PMID:30606148). BRCA2: c.3680_3681delTG (rs80359395) is rare in population databases (gnomAD=0.01%) and is not on record in FLOSSIES. This variant is on record in ClinVar reported by multiple clinical laboratories as pathogenic in association with Breast-ovarian cancer, familial 2, Hereditary cancer-predisposing syndrome, and Hereditary breast and ovarian cancer syndrome (Variation ID:51504). This variant is listed in HGMD as ‘disease causing mutation’ in association with Ovarian cancer (Accession: CD011120). -
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	Sharing Clinical Reports Project (SCRP)	Mar 12, 2013	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 17, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	research	Laan Lab, Human Genetics Research Group, University of Tartu	May 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change creates a premature translational stop signal (p.Leu1227Glnfs*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 present in population databases (rs80359395, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11179017, 22762150, 24013928, 24728189, 24916970, 26845104, 27356891). This variant is also known as 3908_3909delTG. ClinVar contains an entry for this variant (Variation ID: 51504). 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	Nov 05, 2020	Variant summary: BRCA2 c.3680_3681delTG (p.Leu1227GlnfsX5) 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 249486 control chromosomes (gnomAD). c.3680_3681delTG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Peto_1999, Risch_2001, Miramar_2008, Lecarpentier_2012, Pal_2014). These data indicate that the variant is very likely to be associated with disease. Ten ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This frameshifting variant in exon 11 of 28 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with breast and/or ovarian cancer (PMID: 11179017; 24013928; 25186627; 30159786). The c.3680_3681del variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.00003% (1/31392) and thus is presumed to be rare. Based on the available evidence, the c.3680_3681del variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2019	The p.Leu1227GlnfsX5 variant in BRCA2 has been reported in at least 8 individuals with BRCA2-associated cancers (Peto 1999, Risch 2001, Pal 2014, Breast Cancer Information Core (BIC) database). It has also been identified in 1/8710 African chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1227 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282380.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP criteria applied: PVS1, PS4_Moderate, PM2. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2021	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 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 3908_3909delTG; This variant is associated with the following publications: (PMID: 11179017, 26845104, 24013928, 27356891, 26287763, 22762150, 24916970, 23315985, 20167696, 24728189, 28127413, 28152038, 29907814, 29470806, 25186627, 28993434, 30606148, 30159786, 30720243, 31263054, 33654310, 31589614, 32427313, 30787465, 33087929) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Leu1227Glnfs*5 variant was identified in 7 of 12390 proband chromosomes (frequency: 0.00056) from individuals or families with colorectal, breast or ovarian cancer (Dobbins 2016, Palmero 2018, Peixoto 2015, Shirts 2016, Song 2014). The variant was also identified in the following databases: dbSNP (ID: rs80359395) as "With Pathogenic allele ", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and nine clinical laboratories), LOVD 3.0 (9x as pathogenic), UMD-LSDB (3x as causal ), BIC Database (8x with clinical importance), and in ARUP Laboratories (definitely pathogenic). The variant was not identified in Cosmic, Zhejiang University, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3680_3681del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1227 and leads to a premature stop codon at position 1231. 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 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 11, 2020	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 and colorectal cancer in the published literature (PMIDs: 11179017 (2001), 24013928 (2014), 26287763 (2015), 27356891 (2016), 28993434 (2018), 29470806 (2018), 30159786 (2018), and 30606148 (2019)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 17, 2021	The c.3680_3681delTG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at positions 3680 to 3681, causing a translational frameshift with a predicted alternate stop codon (p.L1227Qfs*5). This alteration has been reported in numerous ancestrally diverse individuals with a personal and/or family history of breast and/or ovarian cancer (Peto J et al. J. Natl. Cancer Inst. 1999 Jun;91:943-9; Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Miramar MD et al. Breast Cancer Res Treat. 2008 Nov;112:353-8; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Pal T et al. Cancer. 2015 Dec;121:4173-80; Peixoto A et al. Clin Genet. 2015 Jul;88:41-8; Singh J et al. Breast Cancer Res Treat. 2018 Jul;170:189-196; Wen WX et al. J Med Genet. 2018 02;55:97-103; Cotrim DP et al. BMC Cancer. 2019 Jan;19:4; Petridis C et al. Cancer Epidemiol Biomarkers Prev. 2019 07;28:1162-1168; Santonocito C et al. Cancers (Basel). 2020 May;12:; Sandoval RL et al. PLoS One. 2021 Feb;16:e0247363). In addition, this alteration was reported in one individual with a personal history of early-onset familial colorectal cancer (Dobbins SE et al. Fam. Cancer 2016 Oct;15(4):593-9). Of note, this alteration is also designated as 3908delTG and 3908_3909delTG 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	Mar 15, 2023	This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3908delTG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 10359546, 11179017, 16826315, 18176857, 21324516, 22711857, 22762150, 24013928, 24916970, 26845104) and one individual each affected with endometrial and colorectal cancer (PMID: 24728189, 27356891). This variant has been identified in 1/31392 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	Dec 07, 2021	- -

BRCA2-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 29, 2023	The BRCA2 c.3680_3681delTG variant is predicted to result in a frameshift and premature protein termination (p.Leu1227Glnfs*5). This variant (also known as c.3908_3909delTG) has been reported as pathogenic in multiple individuals with a history of hereditary cancer syndromes (Song et al. 2014. PubMed ID: 24728189. Table S1; Risch et al. 2001. PubMed ID: 11179017; Pal et al. 2014. PubMed ID: 24013928; Dobbins et al. 2016. PubMed ID: 27356891;Bennett et al. 2021. PubMed ID: 33654310. Table S1). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32912171-CTG-C). It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51504/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Aug 10, 2022	The c.3680_3681del;p.(Leu1227Glnfs*5) is a null frameshift variant (NMD) in the BRCA2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 51504; PMID: 24013928; 11179017; 24916970; 24728189; 22762150; 2684510) - PS4. The variant is present at low allele frequencies population databases (rs80359395 – gnomAD 0.00006573%; ABraOM no frequency - https://abraom.ib.usp.br/) -PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 24013928; 11179017; 24916970; 24728189; 22762150) -PP1. In summary, the currently available evidence indicates that the variant is pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 27, 2024

- -

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: rs80359395; hg19: chr13-32912171;