Submissions for variant NM_000059.4(BRCA2):c.2570dup (p.Arg858fs)

dbSNP: rs587782361

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241017	SCV000300531	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000131317	SCV000186290	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-20	criteria provided, single submitter	clinical testing	The c.2570dupT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 2570, causing a translational frameshift with a predicted alternate stop codon (p.R858Kfs*23). This mutation has been identified in a cohort of Chinese breast cancer patients (Sun et al. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV000274423	SCV000329606	pathogenic	not provided	2016-02-22	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in BRCA2 is denoted c.2570dupT at the cDNA level and p.Arg858LysfsX23 (R858KfsX23) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 2798dupT. The normal sequence, with the base that is duplicated in brackets, is AATC[T]AAGA. The duplication causes a frameshift, which changes an Arginine to a Lysine at codon 858, and creates a premature stop codon at position 23 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496214	SCV000836805	pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg858Lysfs*23) 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: 28724667). ClinVar contains an entry for this variant (Variation ID: 142288). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131317	SCV000905179	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-11	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 11 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 been reported in one individual affected with breast cancer (PMID: 28724667). 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.
Revvity Omics, Revvity	RCV000274423	SCV003810510	pathogenic	not provided	2022-12-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567131	SCV005059121	pathogenic	Familial cancer of breast	2024-01-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000274423	SCV005624361	pathogenic	not provided	2024-11-17	criteria provided, single submitter	clinical testing	The BRCA2 c.2570dup (p.Arg858Lysfs*23) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in an individual with breast cancer (PMID: 28724667 (2017)). 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.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496214	SCV000587635	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research