rs80359560

chr13-32326589-AC-Achr13-32326589-AC-ACC

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.610del(p.Ser205ValfsTer6) variant causes a frameshift change. 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. T203T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 5.30

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 13-32326589-AC-A is Pathogenic according to our data. Variant chr13-32326589-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 52015.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32326589-AC-A is described in Lovd as [Pathogenic]. Variant chr13-32326589-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.610del	p.Ser205ValfsTer6	frameshift_variant	7/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.610del	p.Ser205ValfsTer6	frameshift_variant	7/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3

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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant deletes 1 nucleotide in exon 7 of the BRCA2 gene, creating a frameshift and 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 14, 2022	The c.610delC pathogenic mutation, located in coding exon 6 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 610, causing a translational frameshift with a predicted alternate stop codon (p.S205Vfs*6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation (designated as 838delC) has been identified in a woman with contralateral breast cancer, in which her primary breast cancer was diagnosed under the age of 54 (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Ser205Valfs*6) 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 contralateral breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 52015). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2023	Variant summary: BRCA2 c.610delC (p.Ser205ValfsX6) 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 251368 control chromosomes (gnomAD). c.610delC has been reported in the literature in at least one individual affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Borg_2010). Experimental evidence from one publication has shown that alternative splicing of BRCA2 can restore the ORF, specifically when the variant of interest is found on a transcript missing exon 5, which typically results in a frameshift (Stauffer_2020). Since this ORF restoration necessitates the splicing of a typically degraded transcript, this result does not allow convincing conclusions about the variants effect on the risk of developing breast cancer. The following publications have been ascertained in the context of this evaluation (PMID: 20104584, 29446198, 32393813). Six ClinVar submitters, including one expert panel (ENIGMA), have assessed the variant since 2014: all six classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 17, 2022

Frameshift variant demonstrated to result in multiple isoforms that are predicted to undergo protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Stauffer 2020); Observed in an individual with breast cancer (Borg 2010); 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 838delC; This variant is associated with the following publications: (PMID: 23983145, 20104584, 32393813) -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The BRCA2 p.Ser205ValfsX6 variant was identified in 1 of 4206 proband chromosomes (frequency: 0.000) from individuals with breast cancer in a population based sample study (Borg, 2006). The variant was identified in dbSNP (ID: rs80359560) “With pathogenic allele”. It was also identified in HGMD, the BIC database (1X as pathogenic) and the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) 2x (1X from BIC as a pathogenic variant, and 1X by Invitae, classification not provided). The deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 205 and leads to a premature stop codon 6 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs80359560; hg19: chr13-32900726;