Submissions for variant NM_000059.4(BRCA2):c.4562_4563delinsCG (p.Leu1521Pro)

dbSNP: rs1555283849

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254767	SCV000322532	uncertain significance	not provided	2017-11-03	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.4562_4563delTAinsGC at the cDNA level and p.Leu1521Pro (L1521P) at the protein level. The normal sequence, with the bases that are deleted and inserted in brackets, is ACTC[delTA][insCG]TTGG. This in-frame deletion and insertion, also denoted BRCA2 4790_4791delTAinsCG using alternate nomenclature, occurs on the same allele (in cis) and results in the missense change of a Leucine to a Proline (CTA>CCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Neither BRCA2 c.4562_4563delTAinsGC nor BRCA2 Leu1521Pro (by this or an alternate nucleotide change) was observed in large population cohorts (Lek 2016). Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Leu1521Pro occurs at a position that is not conserved and is located within the 4th BRC repeat as well as in the region of interaction with POLH and RAD51 (Cole 2011, Roy 2012, Buisson 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, we consider BRCA2 Leu1521Pro to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544731	SCV000635380	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-11	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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 265549). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1521 of the BRCA2 protein (p.Leu1521Pro).
Ambry Genetics	RCV001022703	SCV001184470	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-11	criteria provided, single submitter	clinical testing	The c.4562_4563delTAinsCG variant (also known as p.L1521P), located in coding exon 10 of the BRCA2 gene, results from an in-frame deletion of TA and insertion of CG at nucleotide positions 4562 to 4563. This results in the substitution of the leucine residue for a proline residue at codon 1521, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001022703	SCV003847522	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055813	SCV005726633	uncertain significance	not specified	2024-11-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4562_4563delinsCG (p.Leu1521Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found as a multinucleotide variant (13-32913054-TA-CG) in the gnomAD database at a frequency of 8e-06 in 250602 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.4562_4563delinsCG in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 265549). Based on the evidence outlined above, the variant was classified as uncertain significance.