Submissions for variant NM_000059.4(BRCA2):c.7655_7658del (p.Ile2552fs)

dbSNP: rs80359669

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113803	SCV000301186	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113803	SCV000327705	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000479230	SCV000568484	pathogenic	not provided	2016-08-31	criteria provided, single submitter	clinical testing	This deletion of four nucleotides in BRCA2 is denoted c.7655_7658delTTAA at the cDNA level and p.Ile2552ThrfsX95 (I2552TfsX95) at the protein level. The normal sequence, with the bases that are deleted in braces, is TAAAAA[TTAA]CAGC. The deletion causes a frameshift which changes an Isoleucine to a Threonine at codon 2552, and creates a premature stop codon at position 95 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Also reported as BRCA2 7883delTTAA using alternate nomenclature, this variant has been observed in at least one individual with early-onset breast cancer (Zhi 2002). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479230	SCV001133913	pathogenic	not provided	2019-07-09	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496252	SCV002245805	pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile2552Thrfs*95) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52378). This premature translational stop signal has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 30214756, 30702160, 32658311). This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV002390191	SCV002671792	pathogenic	Hereditary cancer-predisposing syndrome	2024-04-01	criteria provided, single submitter	clinical testing	The c.7655_7658delTTAA pathogenic mutation, located in coding exon 15 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 7655 to 7658, causing a translational frameshift with a predicted alternate stop codon (p.I2552Tfs*95). This alteration was identified in a Turkish family with early-onset breast cancer (Celik E et al. Clin Case Rep, 2018 Sep;6:1751-1755). This alteration was also identified in multiple studies of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973). 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113803	SCV000147157	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496252	SCV000587901	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research