chr13-32371040-C-T

Position:

• chr13-32371040-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.8572C>T​(p.Gln2858Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000132 in 151,986 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q2858Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 4.40

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 13-32371040-C-T is Pathogenic according to our data. Variant chr13-32371040-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 52624.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32371040-C-T is described in Lovd as [Pathogenic]. Variant chr13-32371040-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8572C>T	p.Gln2858Ter	stop_gained	20/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8572C>T	p.Gln2858Ter	stop_gained	20/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151986 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151986 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74230

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000156 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jun 22, 1999	- -
Pathogenic, criteria provided, single submitter	research	Institute of Genomics, University of Tartu	-	- -
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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

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	Mar 27, 2022	ClinVar contains an entry for this variant (Variation ID: 52624). This variant is also known as C8800T. This premature translational stop signal has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 10449599, 25066507). This variant is present in population databases (rs80359112, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Gln2858*) 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). For these reasons, this variant has been classified as Pathogenic. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Gln2858x variant has been identified as a clinically significant mutation in 1 out of 92 proband chromosomes (frequency 0.011) from individuals with a breast and ovarian cancer phenotype, however no controls were included in this study (Santarosa 1999). It is listed in the dbSNP database as coming from a “clinical source” (ID#: rs80359112), but no frequency information was available. The p.Gln2858X variant leads to a premature stop codon at position 2858, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast cancer patients. In summary, based on the above information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2021

The p.Q2858* pathogenic mutation (also known as c.8572C>T), located in coding exon 19 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8572. This changes the amino acid from a glutamine to a stop codon within coding exon 19. This mutation has been identified in several individuals with a personal or family history suggestive of Hereditary Breast and Ovarian Cancer syndrome (Santarosa M et al. Int. J. Cancer, 1999 Sep;83:5-9; Janaviius R et al. Cancer Genet, 2014 May;207:195-205; Labidi-Galy SI et al. Clin Cancer Res, 2018 01;24:326-333; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395). Of note, this mutation may be referred to as 8800C>T in some 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A
Vest4		0.96
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs80359112; hg19: chr13-32945177;