Submissions for variant NM_000059.4(BRCA2):c.10176del (p.Glu3393fs)

dbSNP: rs80359258

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000512982	SCV000608684	uncertain significance	not provided	2022-10-01	criteria provided, single submitter	clinical testing	BRCA2: PM2, PVS1:Supporting
Ambry Genetics	RCV000572053	SCV000666141	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-28	criteria provided, single submitter	clinical testing	The c.10176delA variant, located in coding exon 26 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 10176, causing a translational frameshift with a predicted alternate stop codon (p.E3393Nfs*34). Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of BRCA2, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 26 amino acids of the protein in addition to elongating the protein by 7 amino acids. The exact functional impact of these altered amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000610831	SCV000719024	likely benign	not specified	2017-09-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000512982	SCV002047984	uncertain significance	not provided	2021-10-01	criteria provided, single submitter	clinical testing	The BRCA2 c.10176delA; p.Glu3393AsnfsTer34 variant (rs80359258) is reported in the literature in a large cancer cohort, but without clear association with disease (Huang 2018). This variant is also reported in ClinVar (Variation ID: 37723), but is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the BRCA2 gene. This may not lead to nonsense-mediated decay, and it is expected to create a truncated BRCA2 protein only missing the last 26 amino acids of the protein that would include a sequence of 7 amino acid residues not usually present. Due to limited information, the clinical significance of the p.Glu3393AsnfsTer34 variant is uncertain at this time. References: Huang et al. Pathogenic Germline Variants in 10,389 Adult Cancers. Cell. 2018 Apr 5;173(2):355-370.e14. PMID: 29625052.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002054530	SCV002321104	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the BRCA2 gene (p.Glu3393Asnfs*34). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the BRCA2 protein and extend the protein by 7 additional amino acid residues. This variant is present in population databases (rs746515020, gnomAD 0.0009%). This frameshift has been observed in individual(s) with melanoma (PMID: 29625052, 36451132). ClinVar contains an entry for this variant (Variation ID: 37723). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP)	RCV000031304	SCV000053909	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2006-06-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031304	SCV000145764	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing