rs80359616

Positions:

• chr13-32340998-TACTC-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.6644_6647delACTC​(p.Tyr2215fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,198 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:24
• Conservation: PhyloP100: 0.495

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 13-32340998-TACTC-T is Pathogenic according to our data. Variant chr13-32340998-TACTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 38060.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340998-TACTC-T is described in Lovd as [Pathogenic]. Variant chr13-32340998-TACTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6644_6647delACTC	p.Tyr2215fs	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.6644_6647delACTC	p.Tyr2215fs	frameshift_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6275_6278delACTC	p.Tyr2092fs	frameshift_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6644_6647delACTC		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249524 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134852

Gnomad AFR exome AF: 0.00

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459954 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726116

Gnomad4 AFR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74388

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	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 is also known as 6872del4 in the literature. This variant has been reported in individuals with a personal and/or family history of breast, ovarian cancer, or pancreatic cancer (PMID: 9150172, 11179017, 11179017, 11597388, 16683254, 18284688, 21324516, 29084914, 29446198, 29625052, 29922827). This variant has been identified in 1/249524 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	clinical testing	Counsyl	Apr 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
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, 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)	May 01, 2012	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 26, 2019	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been seen in affected individuals with ovarian cancer in the published literature (PMIDs: 21324516 (2011), 22144684 (2012), 29084914 (2018), and 30720243 (2019)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 21, 2020	The BRCA2 c.6644_6647delACTC; p.Tyr2215fs variant (rs80359616), also known as c.6872del4, is reported in the literature in several individuals with breast and/or ovarian cancer (Caputo 2012, Serova-Sinilnikova 1997, Zhang 2011). This variant is also reported in ClinVar (Variation ID: 38060). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Caputo S et al. Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. Nucleic Acids Res. 2012;40(Database issue):D992-1002. Serova-Sinilnikova OM et al. BRCA2 mutations in hereditary breast and ovarian cancer in France. Am J Hum Genet. 1997 May;60(5):1236-9. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011;121(2):353-7. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 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; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Serova-Sinilnikova 1997, Verhoog 1999, Risch 2001, Verhoog 2001, Lewis 2006, Zhang 2011, Caputo 2012, Tung 2015, Johnson 2017, Labidi-Galy 2018); 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 6872_6875delACTC; This variant is associated with the following publications: (PMID: 11179017, 29625052, 9150172, 16683254, 21324516, 22144684, 26586665, 26926684, 16541310, 22019625, 11597388, 21120943, 25186627, 28526081, 28476184, 15131399, 29084914, 10550133, 30720243) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2020	PVS1, PM2, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 27, 2017	The p.Tyr2215fs variant in BRCA2 has been reported in >25 individuals with BRCA2 -associated cancers and segregated with disease in 5 relatives from 2 families ( Serova-Sinilnikova 1997, Caputo 2012, Zhang 2011, Risch 2001, Verhoog 2001, and Breast Cancer Information Core (BIC) database). It was also absent from large po pulation studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 2215 and leads to a prem ature termination codon 13 amino acids downstream. This alteration is then predi cted 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 ovar ian cancer (HBOC). In addition, this variant was classified as Pathogenic on Sep tember 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000301085 .2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 05, 2019	Variant summary: The variant, BRCA2 c.6644_6647delACTC (p.Tyr2215SerfsX13) 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 (eg. c.6682dupG(p.Val2228fsX5), c.6757_6758delCT(p.Leu2253fsX7)). The variant allele was found at a frequency of 4.1e-06 in 244534 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with breast cancer, ovarian cancer and pancreatic cancer (Caputo_2012, Lee_2008, Hu_2018, Zhang_2011). 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. Ten ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	This sequence change creates a premature translational stop signal (p.Tyr2215Serfs*13) 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 (rs80359616, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150172, 16683254, 21120943, 21324516, 22144684). This variant is also known as 6872del4 or 6872delACTC. ClinVar contains an entry for this variant (Variation ID: 38060). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 02, 2024	The c.6644_6647delACTC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 6644 to 6647, causing a translational frameshift with a predicted alternate stop codon (p.Y2215Sfs*13). This mutation has been reported in numerous individuals diagnosed with hereditary breast and ovarian cancer (HBOC) syndrome (Serova-Sinilnikova OM et al. Am. J. Hum. Genet., 1997 May;60:1236-9; Verhoog LC et al. J. Clin. Oncol., 1999 Nov;17:3396-402; Risch HA et al. Am J Hum Genet, 2001 Mar;68:700-10; van der Hout AH et al. Hum Mutat, 2006 Jul;27:654-66; Lewis CM et al. Breast Cancer Res Treat, 2006 Sep;99:103-15; Coulet F et al. Genet Test Mol Biomarkers, 2010 Oct;14:677-90; Zhang S et al. Gynecol Oncol, 2011 May;121:353-7; Caux-Moncoutier V et al. Hum Mutat, 2011 Mar;32:325-34; Caputo S et al. Nucleic Acids Res, 2012 Jan;40:D992-1002; Lecarpentier J et al. Breast Cancer Res, 2012 Jul;14:R99; Labidi-Galy SI et al. Clin Cancer Res, 2018 01;24:326-333). This mutation has also been reported in multiple individuals with pancreatic cancer (Huang KL et al. Cell, 2018 04;173:355-370.e14; Hu C et al. JAMA, 2018 06;319:2401-2409). Of note, this alteration is also designated as 6872del4 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	Aug 28, 2023	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 is also known as 6872del4 in the literature. This variant has been reported in individuals with a personal and/or family history of breast, ovarian cancer, or pancreatic cancer (PMID: 9150172, 11179017, 11179017, 11597388, 16683254, 18284688, 21324516, 29084914, 29446198, 29625052, 29922827). This variant has been identified in 1/249524 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	Jun 16, 2021	- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 26, 2017

- -

BRCA2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2024

The BRCA2 c.6644_6647delACTC variant is predicted to result in a frameshift and premature protein termination (p.Tyr2215Serfs*13). This variant has been reported in several individuals with breast and ovarian cancer (Serova-Sinilnikova et al. 1997. PubMed ID: 9150172; van der Hout et al. 2006. PubMed ID: 16683254; reported as 6872del4 in Zhang et al. 2011. PubMed ID: 21324516). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, it is reported as pathogenic by many genetic testing laboratories and the Evidence-based Network for the Interpretation of Germline Mutant Alleles expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/38060/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80359616; hg19: chr13-32915135;