Submissions for variant NM_000059.4(BRCA2):c.4416_4417del (p.Asn1473fs)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002333852	SCV002633373	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-06	criteria provided, single submitter	clinical testing	The c.4416_4417delGA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 4416 to 4417, causing a translational frameshift with a predicted alternate stop codon (p.N1473Qfs*8). This alteration was identified in 1 of 956 Chinese women undergoing BRCA1 and BRCA2 genetic testing due to a diagnosis of triple negative breast cancer (Wang C et al. Ann Oncol, 2015 Mar;26:523-8). This alteration has been previously published as BRCA2 4644delGA within the literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509831	SCV002819648	pathogenic	Hereditary breast ovarian cancer syndrome	2022-12-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4416_4417delGA (p.Asn1473GlnfsX8) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248776 control chromosomes (gnomAD). c.4416_4417delGA has been reported in the literature in individuals affected with Hereditary Breast And/or Ovarian Cancer (examples: Wang_2015, Sun_2017, and Li_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002509831	SCV004295912	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1473Glnfs*8) 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: 25480878). This variant is also known as 4644delGA (Stop1480). ClinVar contains an entry for this variant (Variation ID: 1740433). For these reasons, this variant has been classified as Pathogenic.