Submissions for variant NM_000059.4(BRCA2):c.7254_7255del (p.Arg2418fs)

dbSNP: rs80359644

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)	RCV000113741	SCV000301147	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.
GeneDx	RCV000220840	SCV000279439	pathogenic	not provided	2016-07-19	criteria provided, single submitter	clinical testing	This deletion of 2 nucleotides in BRCA2 is denoted c.7254_7255delAG at the cDNA level and p.Arg2418SerfsX2 (R2418SfsX2) at the protein level. Using alternate nomenclature, this variant has been reported as BRCA2 7482delAG. The normal sequence, with the bases that are deleted in braces, is ACAG[AG]TTGA. The deletion causes a frameshift, which changes an Arginine to a Serine at codon 2418, and creates a premature stop codon at position 2 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. BRCA2 c.7254_7255delAG has been reported in association with early onset breast cancer in a Nigerian patient (Fackenthal 2012). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113741	SCV000327621	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574102	SCV000665941	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-07	criteria provided, single submitter	clinical testing	The c.7254_7255delAG pathogenic mutation, located in coding exon 13 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 7254 to 7255, causing a translational frameshift with a predicted alternate stop codon (p.R2418Sfs*2). This alteration has been identified in individuals diagnosed with breast cancer (Fackenthal JD et al. Int J Cancer, 2012 Sep;131:1114-23; Yadav S et al. J Clin Oncol, 2020 05;38:1409-1418). 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.
Color Diagnostics, LLC DBA Color Health	RCV000574102	SCV000683859	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 14 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 5 individuals affected with breast cancer, including 1 individual with early-onset breast cancer and 1 individual with triple-negative breast cancer (PMID: 22034289, 31325073, 32125938, DOI: 10.24075/brsmu.2021.006). This variant has been identified in 1/31410 chromosomes 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.
Invitae	RCV001225159	SCV001397398	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2418Serfs*2) 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: 22034289). This variant is also known as 7482delAG. ClinVar contains an entry for this variant (Variation ID: 52300). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000220840	SCV001469705	pathogenic	not provided	2020-08-02	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 patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Baylor Genetics	RCV003460608	SCV004216009	pathogenic	Familial cancer of breast	2023-07-18	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113741	SCV000147062	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1999-06-22	no assertion criteria provided	clinical testing