rs80359102

chr13-32370972-C-Achr13-32370972-C-Gchr13-32370972-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.8504C>A(p.Ser2835Ter) 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. S2835S) 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:9
• Conservation: PhyloP100: 1.86

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 13-32370972-C-A is Pathogenic according to our data. Variant chr13-32370972-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 52607.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370972-C-A is described in Lovd as [Pathogenic]. Variant chr13-32370972-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8504C>A	p.Ser2835Ter	stop_gained	20/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8504C>A	p.Ser2835Ter	stop_gained	20/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

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)	Dec 23, 2003	- -
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, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 21, 2021	The p.S2835* pathogenic mutation (also known as c.8504C>A), located in coding exon 19 of the BRCA2 gene, results from a C to A substitution at nucleotide position 8504. This changes the amino acid from a serine to a stop codon within coding exon 19. This mutation has been reported in multiple Asian individuals with personal and family histories of breast and/or ovarian cancer (Ikeda N et al. Int J Cancer, 2001 Jan;91:83-8; Sakayori M et al. J. Hum. Genet. 2003;48(3):130-7; Sugano K et al. Cancer Sci. 2008 Oct;99(10):1967-76; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Arai M et al. J Hum Genet, 2018 Apr;63:447-457; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Li JY et al. Int J Cancer, 2019 01;144:281-289; Liu Y et al. Mol Genet Genomic Med, 2019 03;7:e493). This mutation has also been reported with a carrier frequency of 0.00013 in 7,636 unselected prostate cancer patients and 0.00000 in 12,366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). This mutation has also been detected in conjunction with a second BRCA2 mutation in a Japanese patient with Fanconi anemia and associated acute myeloid leukemia (Howlett NG et al. Science. 2002 Jul;297(5581):606-9; Ikeda H et al. Cancer Res. 2003 May;63(10):2688-94). Of note, this alteration is also designated as 8732C>A in 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 27, 2020	This variant changes 1 nucleotide in exon 20 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A cell line from a compound heterozygous BRCA2 carrier with this variant tested positive for chromosomal breakage after mitomycin-C treatment and reduced mRNA transcript levels (PMID: 24395671, 30792206). This variant has been reported in at least four Japanese suspected hereditary breast cancer families (PMID: 11149425, 19016756). Haplotype analysis indicates the lack of a common haplotype among the examined carriers (PMID: 11149425). This variant also has been reported in a compound heterozygous BRCA2 mutation carrier affected with Fanconi anemia and leukemia (PMID: 12750298, 24395671). 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

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 04, 2018	Variant summary: BRCA2 c.8504C>A (p.Ser2835X) 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. The variant was absent in 276878 control chromosomes (gnomAD). The variant, c.8504C>A, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, predominantly in Japanese individuals (Ikeda_2001, Inoue_1997). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 22, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52607). This variant is also known as 8732C>A. This premature translational stop signal has been observed in individual(s) with breast cancer and Fanconi anemia (PMID: 12065746, 28724667, 29752822, 30287823). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser2835*) 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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 06, 2019

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	38
Dann	Uncertain	0.99
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.016
FATHMM_MKL	Benign	0.37	N
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs80359102; hg19: chr13-32945109; COSMIC: COSV66448541;