rs397507320

Positions:

• chr13-32325155-T-A

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.396T>A​(p.Cys132*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,394 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: -0.164

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 13-32325155-T-A is Pathogenic according to our data. Variant chr13-32325155-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 37869.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32325155-T-A is described in Lovd as [Pathogenic]. Variant chr13-32325155-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.396T>A	p.Cys132*	stop_gained	4/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.396T>A	p.Cys132*	stop_gained	4/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.27T>A	p.Cys9*	stop_gained	4/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.396T>A		non_coding_transcript_exon_variant	3/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450394 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 722246

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: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

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

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)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 01, 2007	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2017	This variant is denoted BRCA2 c.396T>A at the cDNA level and p.Cys132Ter (C132X) at the proteinlevel. The substitution creates a nonsense variant, which changes a Cysteine to a premature stop codon (TGT>TGA),and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNAdecay. This variant has been observed in at least one individual with early-onset breast cancer (Waddell 2008), and isconsidered pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 03, 2023	The BRCA2 c.396T>A (p.Cys132*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in affected individuals with breast and/or ovarian cancer (PMIDs: 18497862 (2008) and 21702907 (2011)). Functional studies demonstrated that this variant was damaging to protein function (PMIDs: 32393813 (2020) and 32398771 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 23, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 37869). This variant is also known as c.624T>A. This premature translational stop signal has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 18497862, 21702907, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys132*) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.031
FATHMM_MKL	Benign	0.46	N
Vest4		0.67
GERP RS		-0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397507320; hg19: chr13-32899292;