rs375064902

chr13-32340210-T-Achr13-32340210-T-Cchr13-32340210-T-G

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.5855T>A(p.Leu1952Ter) 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: -1.16

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 13-32340210-T-A is Pathogenic according to our data. Variant chr13-32340210-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 38002.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340210-T-A is described in Lovd as [Pathogenic]. Variant chr13-32340210-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5855T>A	p.Leu1952Ter	stop_gained	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5855T>A	p.Leu1952Ter	stop_gained	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3

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	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 18, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 38002). This premature translational stop signal has been observed in individual(s) with increased risk of breast and/or ovarian cancer (PMID: 29446198). This variant is present in population databases (rs375064902, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Leu1952*) 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 13, 2023	The p.Leu1952X variant in BRCA2 has been reported in 1 individual with increased risk of breast and/or ovarian cancer (HBOC; Rebbeck 2018 PMID:29446198) and has also been reported by other clinical laboratories in ClinVar (Variant ID 38002). It was absent from large population studies (gnomAD, v.3.1.2). This nonsense variant leads to a premature termination codon at position 1952, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in individuals with HBOC. Additionally, this variant was classified as pathogenic on Sept. 08, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar: SCV000300942.2). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2_Supporting. -
Likely pathogenic, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2022

The p.L1952* pathogenic mutation (also known as c.5855T>A), located in coding exon 10 of the BRCA2 gene, results from a T to A substitution at nucleotide position 5855. This changes the amino acid from a leucine to a stop codon within coding exon 10. This alteration was identified in two different cohorts unselected for cancer history in unaffected individuals and in one individual with a personal history of breast and ovarian cancers at age 29 (Dorschner MO et al. Am. J. Hum. Genet., 2013 Oct;93:631-40; Natarajan P et al. Sci Transl Med, 2016 Nov;8:364ra151). An alteration resulting in the same stop codon, p.L1952* (6083insAGTT), has also been reported in 1/294 women diagnosed with breast cancer and 0/346 female controls from the Philippines (De Leon Matsuda ML et al, Int. J. Cancer 2002 Apr; 98(4):596-603 ). In addition to the information 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	0.23	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	34
Dann	Uncertain	0.98
Eigen	Benign	-0.038
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.083	N
MutationTaster	Benign	1.0	A;A
Vest4		0.97
GERP RS		-0.073

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: rs375064902; hg19: chr13-32914347; COSMIC: COSV104701368;