Submissions for variant NM_000059.4(BRCA2):c.4574A>C (p.His1525Pro)

gnomAD frequency: 0.00001  dbSNP: rs397507336

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496676	SCV000635382	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1525 of the BRCA2 protein (p.His1525Pro). This variant is present in population databases (rs397507336, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 32885271, 34326862, 35918668). ClinVar contains an entry for this variant (Variation ID: 431191). 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.
Ambry Genetics	RCV000571305	SCV000661353	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-29	criteria provided, single submitter	clinical testing	The p.H1525P variant (also known as c.4574A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 4574. The histidine at codon 1525 is replaced by proline, an amino acid with similar properties. This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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.
Color Diagnostics, LLC DBA Color Health	RCV000571305	SCV000688883	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 1525 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 32885271). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 1/53461 controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008241). This variant has been identified in 3/281922 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800713	SCV002046780	uncertain significance	not provided	2021-03-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001800713	SCV002576142	uncertain significance	not provided	2022-03-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 4802A>C; This variant is associated with the following publications: (PMID: 9002670, 22193408)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000571305	SCV003850626	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	RCV004003493	SCV004845699	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 1525 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 32885271). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 1/53461 controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008241). This variant has been identified in 3/281922 chromosomes 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.
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000496676	SCV000586952	uncertain significance	Hereditary breast ovarian cancer syndrome	2016-04-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357073	SCV001552409	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.His1525Pro variant was not identified in the literature nor was it identified in the following databases: Cosmic, MutDB, LOVD 3.0, UMD-LSDB, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs397507336) as “With Uncertain significance allele”, and in ClinVar (reported 4x, as uncertain significance by Invitae, Ambry, Color Genomics, BC Cancer Agency). The variant was identified in control databases in 3 of 276538 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 3 of 18862 chromosomes (freq: 0.0002), but not in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.His1525Pro residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250642	SCV002520794	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only