Submissions for variant NM_000059.4(BRCA2):c.8255TTC[1] (p.Leu2753del)

dbSNP: rs397507971

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001027327	SCV001189867	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-10	criteria provided, single submitter	clinical testing	The c.8258_8260delTTC variant (also known as p.L2753del) is located in coding exon 17 of the BRCA2 gene. This variant results from an in-frame deletion of TTC at nucleotide positions 8258 to 8260. This results in the in-frame deletion of a leucine at codon 2753. One group has reported that this alteration may have an impact on splicing, as the variant modified the alternative splicing of exon 18 (coding exon 17), however transcripts lacking this exon were also present in controls, therefore the clinical consequences of this finding could not be conclusively determined based on this study (Bonnet C et al. J. Med. Genet., 2008 Jul;45:438-46; Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This nucleotide region is not well conserved in available vertebrate species. In addition, the in silico prediction for the single amino acid deletion resulting from this alteration is inconclusive (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.
Baylor Genetics	RCV000577411	SCV004213695	uncertain significance	Familial cancer of breast	2023-08-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003529943	SCV004297184	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-04	criteria provided, single submitter	clinical testing	This variant, c.8258_8260del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Leu2753del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs779336144, gnomAD 0.006%). This variant has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 18424508). This variant is also known as c.8257_8259delCTT (p.Leu2753del). ClinVar contains an entry for this variant (Variation ID: 52539). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Studies have shown that this variant is associated with inconclusive levels of altered splicing (PMID: 18424508). 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.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577411	SCV000678822	not provided	Familial cancer of breast		no assertion provided	literature only