Submissions for variant NM_000059.4(BRCA2):c.10248dup (p.Tyr3417fs)

dbSNP: rs776212316

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002080236	SCV002324172	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-14	criteria provided, single submitter	clinical testing	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. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs776212316, gnomAD 0.003%). This sequence change results in a frameshift in the BRCA2 gene (p.Tyr3417Ilefs*21). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the BRCA2 protein and extend the protein by 18 additional amino acid residues.
Mendelics	RCV002246666	SCV002518003	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
GeneDx	RCV003126110	SCV003803427	uncertain significance	not provided	2022-08-12	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation as the last 2 amino acids are replaced with 20 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Located in a region that tolerates variation and lacks pathogenic variants; Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 10476dupA
Ambry Genetics	RCV003161329	SCV003882369	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-02	criteria provided, single submitter	clinical testing	The c.10248dupA variant, located in coding exon 26 of the BRCA2 gene, results from a duplication of A at nucleotide position 10248, causing a translational frameshift with a predicted alternate stop codon (p.Y3417Ifs*21). This alteration occurs at the 3' terminus of the BRCA2 gene, is not expected to trigger nonsense-mediated mRNA decay and results in the elongation of the protein by 18 amino acids. This frameshift impacts the last 2 amino acids of the native protein. The exact functional effect of the altered amino acids is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.