Submissions for variant NM_000059.4(BRCA2):c.4574A>T (p.His1525Leu)

dbSNP: rs397507336

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001040512	SCV001204091	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1525 of the BRCA2 protein (p.His1525Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 33067490). ClinVar contains an entry for this variant (Variation ID: 838870). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001524520	SCV001734407	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-19	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with leucine at codon 1525 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). 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.
GeneDx	RCV001776098	SCV002013984	uncertain significance	not provided	2019-05-28	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 33067490)
University of Washington Department of Laboratory Medicine, University of Washington	RCV001524520	SCV003850624	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).
All of Us Research Program, National Institutes of Health	RCV004004732	SCV004845700	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with leucine at codon 1525 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). 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.
Ambry Genetics	RCV001524520	SCV005551885	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-11	criteria provided, single submitter	clinical testing	The p.H1525L variant (also known as c.4574A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 4574. The histidine at codon 1525 is replaced by leucine, an amino acid with similar properties. This variant was detected in a cohort of 200 Jordanian patients with breast and/or ovarian cancers (Abu-Helalah M et al. Sci Rep, 2020 Oct;10:17573). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.