rs397507994

chr13-32371060-C-CT

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.8594dup(p.Leu2865PhefsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. A2864A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 0.524

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 13-32371060-C-CT is Pathogenic according to our data. Variant chr13-32371060-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 52631.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8594dup	p.Leu2865PhefsTer4	frameshift_variant	20/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8594dup	p.Leu2865PhefsTer4	frameshift_variant	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:10

Revision: reviewed by expert panel

Submissions by phenotype

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

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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Oct 29, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 02, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 10, 2012	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2019	Frameshift 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; Not observed in large population cohorts (Lek et al., 2016); Also known as BRCA2 8822insT and 8821insT; This variant is associated with the following publications: (PMID: 20104584, 20927582, 23179792, 28152038, 29922827) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 15, 2021	This frameshift variant causes the premature termination of BRCA2 protein synthesis. It has been reported in individuals affected with breast cancer in the published literature (PMID: 23179792 (2013), 20927582 (2011), 20104584 (2010)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 28, 2023	This sequence change creates a premature translational stop signal (p.Leu2865Phefs*4) 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 BRCA2-related conditions (PMID: 20104584). This variant is also known as 8823insT. ClinVar contains an entry for this variant (Variation ID: 52631). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 18, 2023	Variant summary: The variant, BRCA2 c.8594dupT (p.Leu2865PhefsX4) 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 245972 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with breast cancer and pancreatic cancer (Borg_2010, Ding_2011, Nelson-Moseke_2013, Hu_2018). These data indicate that the variant is very likely to be associated with Hereditary breast and ovarian cancer syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20104584, 20927582, 23179792, 29922827). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 08, 2023

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2020

The c.8594dupT pathogenic mutation, located in coding exon 19 of the BRCA2 gene, results from a duplication of T at nucleotide position 8594, causing a translational frameshift with a predicted alternate stop codon (p.L2865Ffs*4). In one large study, this mutation was observed in 1 of 705 patients with contralateral breast cancer and not in any of the 1398 patients with unilateral breast cancer (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40). In another study, this mutation was detected in a Hispanic male diagnosed with breast cancer (Ding YC et al. Breast Cancer Res. Treat. 2011 Apr;126:771-8). Of note, this mutation is also designated as 8822insT 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs80359721; hg19: chr13-32945197;