rs80359752

chr13-32380135-GA-Gchr13-32380135-GA-GAA

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.9253del(p.Thr3085GlnfsTer19) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000658 in 151,972 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. K3083K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 4.00

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 13-32380135-GA-G is Pathogenic according to our data. Variant chr13-32380135-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 52785.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32380135-GA-G is described in Lovd as [Pathogenic]. Variant chr13-32380135-GA-G is described in Lovd as [Pathogenic]. Variant chr13-32380135-GA-G is described in Lovd as [Pathogenic]. Variant chr13-32380135-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9253del	p.Thr3085GlnfsTer19	frameshift_variant	24/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9253del	p.Thr3085GlnfsTer19	frameshift_variant	24/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151972 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458716 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725646

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151972 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74222

Gnomad4 AFR AF: 0.0000242

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: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	research	Center of Medical Genetics and Primary Health Care	Apr 08, 2020	The BRCA2 variant p.Thr3085Glnfs is a known pathogenic variant in exon 23 in the Nucleic acid-binding OB-fold (T2968-3184L aa) domain and in a mutation hotspot of 16 pathogenic variants (PM1 Pathogenic Moderate). This frameshift variant disrupts the function of the domain (PVS1 Pathogenic Very Strong). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). 1 pathogenic prediction from GERP versus no benign predictions supports its deleterious effect (PP3 Pathogenic Supporting). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000324753.1) (PP5 Pathogenic Supporting). In our study the variant p.Thr3085Glnfs was found in a 41-year-old female with unilateral breast cancer with a family history of cancer. -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Oct 18, 2016	Variant allele predicted to encode a truncated non-functional protein. -
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, criteria provided, single submitter	clinical testing	Baylor Genetics	May 30, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2019	PVS1, PM2, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2022	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; Identified in multiple individuals with a personal or family history of breast cancer (Malone 2006, Kim 2012, Son 2012, Ou 2013, Kang 2015, Kim 2016, Park 2017); 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 9481delA; This variant is associated with the following publications: (PMID: 22382806, 23593081, 26187060, 25863477, 22798144, 26848529, 16912212, 28205045, 28111427, 30787465, 30014164, 30702160, 33558524, 31825140) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 25, 2023	The BRCA2 c.9253del (p.Thr3085Glnfs*19) variant has been reported in the published literature in individuals and families affected with breast cancer (PMIDs: 23593081 (2013), 25863477 (2015), 28205045 (2017), 37239058 (2023)) and prostate cancer (PMID: 37118955 (2023)). The frequency of this variant in the general population, 0.0000066 (1/151972 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2022	Variant summary: BRCA2 c.9253delA (p.Thr3085GlnfsX19) 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. This variant is also known as c.9481delA. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248582 control chromosomes (gnomAD). c.9253delA has been reported in the literature in individuals affected with Hereditary Breast And/or Ovarian Cancer (example: Kang_2017). These data indicate that the variant is likely to be associated with disease. Nine submitters including an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change creates a premature translational stop signal (p.Thr3085Glnfs*19) 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 cancer (PMID: 22382806, 23593081, 25863477). This variant is also known as 9481delA. ClinVar contains an entry for this variant (Variation ID: 52785). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 27, 2017	The p.Thr3085fs variant in BRCA2 has been reported in at least 7 individuals wit h BRCA2-associated cancers (Kim 2012, Son 2012, Ou 2013, Kang 2015 ) and was abs ent from large population studies. This variant is predicted to cause a frameshi ft, which alters the protein?s amino acid sequence beginning at position 3085 an d leads to a premature termination codon 19 amino acids downstream. This alterat ion is then predicted to lead to a truncated or absent protein. Heterozygous los s of function of the BRCA2 gene is an established disease mechanism in hereditar y breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on October 18, 2016 by the ClinGen-approved ENIGMA expert panel (Clin Var SCV000324753.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2022

The c.9253delA pathogenic mutation, located in coding exon 23 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 9253, causing a translational frameshift with a predicted alternate stop codon (p.T3085Qfs*19). This mutation has been reported in several Korean breast cancer patients (Son BH et al. Breast Cancer Res. Treat. 2012 Jun;133:1143-52; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Park B et al. Breast Cancer Res. Treat. 2017 May;163(1):139-150). Another study identified this mutation in one Kazakh Chinese individual in a cohort of 32 Chinese breast cancer patients diagnosed at age 35 or younger (Ou J et al. J Breast Cancer 2013 Mar;16:50-4). Of note, this alteration is also designated as 9481delA 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. -

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: rs80359752; hg19: chr13-32954272;