Submissions for variant NM_000059.4(BRCA2):c.4216_4218del (p.Lys1406del)

dbSNP: rs758636052

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165913	SCV000216668	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-07	criteria provided, single submitter	clinical testing	The c.4216_4218delAAA variant (also known as p.K1406del) is located in coding exon 10 of the BRCA2 gene. This variant results from an in-frame AAA deletion at nucleotide positions 4216 to 4218. This results in the in-frame deletion of a lysine at codon 1406. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000222837	SCV000279471	uncertain significance	not provided	2015-10-06	criteria provided, single submitter	clinical testing	This in-frame deletion of 3 nucleotides in BRCA2 is denoted c.4216_4218delAAA at the cDNA level and p.Lys1406del (K1406del) at the protein level. Using alternate nomenclature, this variant would be described as BRCA2 4444_4446delAAA. The normal sequence, with the bases that are deleted in braces, is AAAT[AAA]GAAC. This deletion of a single Lysine residue occurs at a position that is not conserved and is within the region of interaction with POLH (UniProt). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider BRCA2 Lys1406del to be a variant of uncertain significance.
Counsyl	RCV000662987	SCV000785973	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001362079	SCV001558080	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-15	criteria provided, single submitter	clinical testing	This variant, c.4216_4218del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Lys1406del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758636052, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 186334). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.