Submissions for variant NM_000059.4(BRCA2):c.5272_5286del (p.Asn1758_Tyr1762del)

dbSNP: rs758071261

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480780	SCV000567998	uncertain significance	not provided	2018-05-04	criteria provided, single submitter	clinical testing	This in-frame deletion of 15 nucleotides in BRCA2 is denoted c.5272_5286del15 at the cDNA level and p.Asn1758_Tyr1762del (N1758_Y1762del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ATAT[del15]CTCT. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). This deletion is located in within the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect.? However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. 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 Asn1758_Tyr1762del to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001233021	SCV001405598	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-29	criteria provided, single submitter	clinical testing	This variant, c.5272_5286del, results in the deletion of 5 amino acid(s) of the BRCA2 protein (p.Asn1758_Tyr1762del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758071261, gnomAD 0.007%). 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: 419860). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553669	SCV001774609	uncertain significance	not specified	2021-08-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5272_5286del15 (p.Asn1758_Tyr1762del) results in an in-frame deletion that is predicted to remove five amino acids from the encoded protein. The variant allele was found at a frequency of 4e-06 in 250332 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5272_5286del15 in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004003310	SCV004826994	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480780	SCV005624452	uncertain significance	not provided	2024-03-15	criteria provided, single submitter	clinical testing	The BRCA2 c.5272_5286del (p.Asn1758_Tyr1762del) variant has not been reported in individuals with BRCA2-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/250332 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.