Submissions for variant NM_000059.4(BRCA2):c.4534C>T (p.Arg1512Cys)

gnomAD frequency: 0.00001  dbSNP: rs80358684

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044428	SCV000072441	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1512 of the BRCA2 protein (p.Arg1512Cys). This variant is present in population databases (rs80358684, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer, malignant melanoma, and stomach cancer (PMID: 26689913, 30286154, 30287823). ClinVar contains an entry for this variant (Variation ID: 51660). 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	RCV000130950	SCV000185864	likely benign	Hereditary cancer-predisposing syndrome	2019-07-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000113312	SCV000785700	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-11-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755874	SCV000883512	uncertain significance	not provided	2017-11-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130950	SCV000903514	likely benign	Hereditary cancer-predisposing syndrome	2017-03-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113312	SCV001271520	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001113729	SCV001271521	uncertain significance	Fanconi anemia complementation group D1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Sema4, Sema4	RCV000130950	SCV002533878	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-01	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000755874	SCV003830139	uncertain significance	not provided	2022-06-09	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153336	SCV003843549	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130950	SCV003850584	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	RCV003230379	SCV003928261	uncertain significance	not specified	2024-08-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4534C>T (p.Arg1512Cys) 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 1.6e-05 in 250336 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4534C>T has been reported in the literature in individuals affected with breast cancer, stomach cancer and malignant melanoma (examples: Momozawa_2018, Lu_2015, Debinak_2018). In one study authors found that the variant did not segregate with the disease (Debinak_2018). 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 publications have been ascertained in the context of this evaluation (PMID: 26689913, 30287823, 30286154). ClinVar contains an entry for this variant (Variation ID: 51660). Based on the evidence outlined above, the variant was classified as uncertain significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV000113312	SCV004047731	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing	The missense variant c.4534C>T (p.Arg1512Cys) in BRCA2 has been submitted to ClinVar as a Variant of Uncertain Significance (VUS). This variant has been observed in individuals affected with breast cancer (Momozawa Y et al). This p.Arg1512Cys variant has allele frequency of 0.0016% in the gnomAD and novel (not in any individuals) in 1000 genome database. The amino acid Arg at position 1512 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS).
All of Us Research Program, National Institutes of Health	RCV000113312	SCV004845691	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000755874	SCV005624434	uncertain significance	not provided	2024-11-18	criteria provided, single submitter	clinical testing	The BRCA2 c.4534C>T (p.Arg1512Cys) variant has been reported in the published literature in individuals with breast cancer (PMID: 30287823 (2018), 34326862 (2021), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)) and stomach cancer (PMID: 26689913 (2015)). This variant has also been identified in reportedly healthy individuals (PMID: 36243179 (2022), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). Additionally, this variant is 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, 0.000016 (4/250336 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113312	SCV000146438	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000755874	SCV001905970	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000755874	SCV001952408	likely benign	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000113312	SCV004243634	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing