Submissions for variant NM_000059.4(BRCA2):c.5189ATC[1] (p.His1731del)

dbSNP: rs1064795583

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484800	SCV000571534	uncertain significance	not provided	2016-08-30	criteria provided, single submitter	clinical testing	This in-frame deletion of 3 nucleotides in BRCA2 is denoted c.5192_5194delATC at the cDNA level and p.His1731del (H1731del) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 c.5420_5422delATC. The normal sequence, with the bases that are deleted in braces, is AATC[ATC]TCTC. This deletion of a single Histidine residue occurs at a position that is not conserved and is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). This variant has not, to our knowledge, been published in the literature as 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 His1731del to be a variant of uncertain significance.
Ambry Genetics	RCV000561386	SCV000666102	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-12	criteria provided, single submitter	clinical testing	The c.5192_5194delATC variant (also known as p.H1731del) is located in coding exon 10 of the BRCA2 gene. This variant results from an in-frame ATC deletion at nucleotide positions 5192 to 5194. This results in the in-frame deletion of a histidine at codon 1731. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001231999	SCV001404540	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-07-25	criteria provided, single submitter	clinical testing	This variant, c.5192_5194del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.His1731del), but otherwise preserves the integrity of the reading frame. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 422140). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency).
Color Diagnostics, LLC DBA Color Health	RCV000561386	SCV001735320	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-12	criteria provided, single submitter	clinical testing	This variant is located in the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.