rs397507845

Positions:

• chr13-32340714-C-G
• chr13-32340714-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.6359C>G​(p.Ser2120*) 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:6
• Conservation: PhyloP100: 0.553

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]

BRCA2 (HGNC:):

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 13-32340714-C-G is Pathogenic according to our data. Variant chr13-32340714-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 52073.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340714-C-G is described in Lovd as [Pathogenic]. Variant chr13-32340714-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6359C>G	p.Ser2120*	stop_gained	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6359C>G	p.Ser2120*	stop_gained	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5990C>G	p.Ser1997*	stop_gained	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6359C>G		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Ser2120X variant was identified in 3 of 4012 proband chromosomes (frequency: 0.0007) from Italian, Chinese and French individuals or families with familial breast and/or ovarian cancers (Palomba 2009, Cao 2016, Caux-Moncoutier 2011). The variant was also identified in dbSNP (ID: rs397507845) “With Pathogenic allele”, ClinVar (classified pathogenic, reviewed by an expert panel (Oct 2016); submitters ENIGMA and CIMBA, and classification not provided by Invitae), Clinvitae (1x), LOVD 3.0 (1x), UMD-LSDB (1x as 5 causal), and ARUP Laboratories (5-definitely pathogenic),. The variant was not identified in Genesight-COGR, Cosmic, MutDB, BIC Database, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Ser2120X variant leads to a premature stop codon at position 2120, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
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	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 21, 2017

This variant is denoted BRCA2 c.6359C>G at the cDNA level and p.Ser2120Ter (S2120X) at the proteinlevel. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA),and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNAdecay. This variant has been reported in families with breast and/or ovarian cancer (Caux-Moncoutier 2011, Li 2014,Cao 2016) and is considered pathogenic -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2020

The p.S2120* pathogenic mutation (also known as c.6359C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 6359. This changes the amino acid from a serine to a stop codon within coding exon 10. This alteration has been associated with personal and family history of breast and ovarian cancer in multiple studies (Palomba G et al. BMC Cancer, 2009 Jul;9:245; Cao WM et al. BMC Cancer, 2015 Feb;16:64; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620; Shi T et al. Int. J. Cancer, 2017 05;140:2051-2059). Of note, this alteration is also designated as 6586C>G 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 24, 2022

This sequence change creates a premature translational stop signal (p.Ser2120*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52073). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 19619314, 21120943, 24961674, 26852015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Uncertain	0.22
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.21	N
Vest4		0.92
GERP RS		1.8

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: rs397507845; hg19: chr13-32914851;