Submissions for variant NM_000059.4(BRCA2):c.4574A>G (p.His1525Arg)

dbSNP: rs397507336

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031490	SCV000267765	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000214334	SCV000276950	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-01	criteria provided, single submitter	clinical testing	The p.H1525R variant (also known as c.4574A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4574. The histidine at codon 1525 is replaced by arginine, an amino acid with highly similar properties. This alteration was detected in 1/2351 Italian breast and/or ovarian cancer patients (Santonocito C et al. Cancers (Basel), 2020 May;12). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229506	SCV000283240	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1525 of the BRCA2 protein (p.His1525Arg). This variant is present in population databases (rs397507336, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 33067490). ClinVar contains an entry for this variant (Variation ID: 37909). 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.
Fulgent Genetics, Fulgent Genetics	RCV002490437	SCV002783593	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-05-13	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000214334	SCV003850625	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998118	SCV005624436	uncertain significance	not provided	2024-06-13	criteria provided, single submitter	clinical testing	The BRCA2 c.4574A>G (p.His1525Arg) variant has been reported in the published literature in an individual with breast cancer and/or ovarian cancer (PMID: 32438681 (2020)), an individual with a personal or family history of unspecified cancer (PMID: 31853058 (2020)) and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000004 (1/250536 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237441	SCV005887714	uncertain significance	not specified	2025-01-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4574A>G (p.His1525Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250536 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4574A>G has been reported in the literature in at least one individual affected with breast or ovarian cancer (Santonocito_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32438681). ClinVar contains an entry for this variant (Variation ID: 37909). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000031490	SCV000054095	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2006-11-14	no assertion criteria provided	clinical testing