ClinVar Miner

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

dbSNP: rs397507336
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Total submissions: 6
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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 2022-07-17 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 variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 37909). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. 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).
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

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