13-32354877-C-T

Position:

• chr13-32354877-C-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.7024C>T​(p.Gln2342Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q2342Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: 3.30

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 13-32354877-C-T is Pathogenic according to our data. Variant chr13-32354877-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 52250.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32354877-C-T is described in Lovd as [Pathogenic]. Variant chr13-32354877-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7024C>T	p.Gln2342Ter	stop_gained	14/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7024C>T	p.Gln2342Ter	stop_gained	14/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250660 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135756

Gnomad AFR exome AF: 0.0000632

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448238 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721260

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 Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
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	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 12, 2018	This rare nonsense variant c.7024C>T, (p.Gln2342Ter) in the BRCA2 gene is rare in public databases (seen once in Gnomad) and is predicted to result in a loss of function of BRCA2. Loss of function variants in BRCA1 are known to be pathogenic for breast cancer. This variant has been observed in multiple unrelated individuals with breast and other cancers (PMID 11836363, 12491487, 19787003). Family history was consistent with mode of iheritance of breast cancer in one family (PMID 19787003). Based upon the above evidence, this c.7024C>T, (p.Gln2342*) variant in BRCA2 is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 07, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Oct 24, 2023	This sequence change creates a premature translational stop signal (p.Gln2342*) 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 (rs80358928, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer and prostate cancer (PMID: 19787003, 28637432). ClinVar contains an entry for this variant (Variation ID: 52250). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jan 23, 2018	- -
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. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2023	Variant summary: BRCA2 c.7024C>T (p.Gln2342X) 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 variant allele was found at a frequency of 4e-06 in 250660 control chromosomes. c.7024C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (example: Couch_2015, Grindedal_2017, Panchal_2009). 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. The following publications have been ascertained in the context of this evaluation (PMID: 25452441, 28637432, 19787003). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2023	This sequence change creates a premature translational stop signal (p.Gln2342*) 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 (rs80358928, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer and prostate cancer (PMID: 19787003, 28637432). ClinVar contains an entry for this variant (Variation ID: 52250). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 09, 2019	- -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 11, 2022	The p.Q2342* pathogenic mutation (also known as c.7024C>T), located in coding exon 13 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7024. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome cohorts, including individuals with male breast and/or prostate cancer (Panchal S et al. Nat Rev Clin Oncol. 2009 Oct;6:604-7; Vesprini D et al. Can Urol Assoc J, 2011 Apr;5:E31-5; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Grindedal EM et al. BMC Cancer. 2017 Jun;17(1):438; Li G et al. J Cancer Res Clin Oncol, 2017 Oct;143:2011-2024; Rebbeck TR et al. Hum. Mutat. 2018 May;39(5):593-620; Bernstein-Molho R et al. Breast Cancer Res Treat, 2019 Nov;178:231-237; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Bang YJ et al. Cancer Res Treat, 2021 Oct). Of note, this alteration is also designated 7252C>T and C7252T in the 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	Feb 28, 2020	This variant changes 1 nucleotide in exon 14 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with female and male breast cancer (PMID: 12491487, 19787003, 21470549, 25452441, 28637432), including one pedigree that had four breast cancer affected siblings with this variant (PMID: 19787003). This variant has been identified in 1/250660 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A;A
Vest4		0.81
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs80358928; hg19: chr13-32929014;