Submissions for variant NM_000059.4(BRCA2):c.4936_4937del (p.Glu1646fs)

dbSNP: rs431825323

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)	RCV000082932	SCV000300802	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	RCV000165590	SCV000216324	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-08	criteria provided, single submitter	clinical testing	The c.4936_4937delGA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 4936 to 4937, causing a translational frameshift with a predicted alternate stop codon (p.E1646Nfs*19). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589045	SCV000694812	pathogenic	Hereditary breast ovarian cancer syndrome	2017-06-20	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.4936_4937delGA (p.Glu1646Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.4965C>G, p.Tyr1655X; c.5042_5043delTG, p.Val1681fs). One in silico tool predicts a damaging outcome for this variant. The variant of interest has not been found in a large, broad control population, ExAC in 119240 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Variant at the same location c.4936_4939delGAAA/p.Glu1646fsX23 has been reported in multiple affected individuals and has been classified as pathogenic by multiple clinical diagnostic laboratories/reputable databases, suggesting the location these variants reside is a mutation hotspot. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758901	SCV000887830	pathogenic	not provided	2018-02-01	criteria provided, single submitter	clinical testing
Invitae	RCV000589045	SCV001381586	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1646Asnfs*19) 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 clinical features of BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 96811). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000758901	SCV003819720	likely pathogenic	not provided	2023-01-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474685	SCV004210360	likely pathogenic	Familial cancer of breast	2023-03-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000758901	SCV004564404	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	The BRCA2 c.4936_4937del; p.Glu1646AsnfsTer19 variant (rs431825323), to our knowledge, is not reported in the medical literature but is reported as pathogenic in ClinVar (Variation ID: 96811). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Other truncating variants at the same position or downstream are reported in patients with breast and/or ovarian cancer and are considered pathogenic (Infante 2006). Based on available information, the c.4936_4937del variant is considered to be pathogenic. References: Infante M et al. High proportion of novel mutations of BRCA1 and BRCA2 in breast/ovarian cancer patients from Castilla-León (central Spain). J Hum Genet. 2006;51(7):611-7. PMID: 16758124.
Sharing Clinical Reports Project (SCRP)	RCV000082932	SCV000115006	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-10-09	no assertion criteria provided	clinical testing