13-32370555-C-T

Variant names:

• chr13-32370555-C-T
• rs80359099
• NM_000059.4:c.8485C>T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.8485C>T​(p.Gln2829*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000206 in 1,456,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 6.08

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 19 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 13-32370555-C-T is Pathogenic according to our data. Variant chr13-32370555-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 52600.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370555-C-T is described in Lovd as [Pathogenic]. Variant chr13-32370555-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8485C>T	p.Gln2829*	stop_gained, splice_region_variant	Exon 19 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8485C>T	p.Gln2829*	stop_gained, splice_region_variant	Exon 19 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8116C>T	p.Gln2706*	stop_gained, splice_region_variant	Exon 19 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*543C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 18 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*543C>T		3_prime_UTR_variant	Exon 18 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456830 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725140

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

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

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 17, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2017

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 21, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q2829* pathogenic mutation (also known as c.8485C>T), located in coding exon 18 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8485. This changes the amino acid from a glutamine to a stop codon within coding exon 18. This pathogenic mutation has been reported in many individuals with or suspected of having hereditary breast and ovarian cancer (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Wang YA et al. BMC Cancer, 2018 03;18:315; Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973; Mehemmai C et al. Pathol Oncol Res, 2020 Apr;26:715-726). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Feb 01, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 28724667, 29202330, 29566657, 30702160). This variant has not been identified 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gln2829X variant in BRCA2 has been reported in at least 6 individuals with hereditary breast and/or ovarian cancer (HBOC; Yang 2015, Shi 2017, Sun 2017, Wang 2018, BIC database). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 2829, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Dec 15, 2017 by the ClinGen-approved ENIGMA expert panel (Variation ID: 52600). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. -

Jul 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln2829*) 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). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 25927356, 28724667, 29446198, 29566657). ClinVar contains an entry for this variant (Variation ID: 52600). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

-

University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: inability to rescue cell lethality in an embryonic stem cell- based assay and absence of protein expression (PMID: 33293522); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 8713C>T; This variant is associated with the following publications: (PMID: 31825140, 30702160, 32341426, 29446198, 28724667, 29566657, 33087929, 31723001, 35226219, 35864222, 30715675, 34235180, 32190957, 26848529, 29202330, 28294317, 32072338, 35216584, 25927356, 28176296, 30720863, 33293522) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	53
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.95
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.16		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: rs80359099; hg19: chr13-32944692;