chr13-32337173-C-T

Position:

• chr13-32337173-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.2818C>T​(p.Gln940*) 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. Q940Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 1.10

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 13-32337173-C-T is Pathogenic according to our data. Variant chr13-32337173-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37804.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337173-C-T is described in Lovd as [Pathogenic]. Variant chr13-32337173-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.2818C>T	p.Gln940*	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.2818C>T	p.Gln940*	stop_gained	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.2449C>T	p.Gln817*	stop_gained	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.2818C>T		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

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)	Feb 20, 2004	- -
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, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 09, 2012	- -
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:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 08, 2019	The p.Gln940X variant in BRCA2 has been previously identified in at least 3 individuals with BRCA2-associated cancer (Breast Information Core Database (BIC), LaDuca 2017, ClinVar) and was absent from large population studies. In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300562.2). This nonsense variant leads to a premature termination codon at position 940 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 hereditary breast and ovarian cancer. In summary, this variant meets criteria to be classified as pathogenic for hereditary breast and ovarian cancer in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PM2, PS4_supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2021	Variant summary: BRCA2 c.2818C>T (p.Gln940X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250674 control chromosomes (gnomAD). The variant c.2818C>T (also known as C3046T) has been reported in the literature in individuals affected with breast cancer (Briceno-Balcazar_2017, Rebbeck_2018). These data indicate that the variant likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change creates a premature translational stop signal (p.Gln940*) 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 cancer (PMID: 29021639). This variant is also known as c.3046C>T. ClinVar contains an entry for this variant (Variation ID: 37804). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2020	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in an individual with a BRCA2-related cancer (Briceno-Balcazar 2017); Not observed in large population cohorts (Lek 2016); Also known as BRCA2 3046C>T; This variant is associated with the following publications: (PMID: 28152038, 29446198, 29021639) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 12, 2023	This variant causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 29021639 (2017)) and ovarian cancer (PMID: 28888541 (2017)). This variant was also identified in an individual with Fanconi Anemia (PMID: 34687993 (2021)). 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 cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 02, 2021	The p.Q940* pathogenic mutation (also known as c.2818C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 2818. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This alteration has been reported in a patient of Asian ancestry from a large cohort of individuals with BRCA1 and BRCA2 mutations (Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). This alteration, designated as C3045T, has also been reported in a cohort of 853 Colombian individuals referred for BRCA1 and BRCA2 testing (Briceño-Balcázar I et al. Colomb. Med., 2017 Jun;48:58-63). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Benign	-0.068
FATHMM_MKL	Benign	0.062	N
Vest4		0.84
GERP RS		4.2

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: rs80358532; hg19: chr13-32911310;