Submissions for variant NM_000059.4(BRCA2):c.4570T>G (p.Phe1524Val)

gnomAD frequency: 0.00004  dbSNP: rs56386506

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083108	SCV000244449	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000208
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081703	SCV000072457	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000044444	SCV000210606	likely benign	not specified	2017-11-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000163006	SCV000213494	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000083108	SCV000488400	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163006	SCV000537475	likely benign	Hereditary cancer-predisposing syndrome	2015-04-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044444	SCV000694782	benign	not specified	2019-10-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4570T>G (p.Phe1524Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250548 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4570T>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Caux-Moncoutier 2009, Haffty 2009, Meyer 2003, Meyer 2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A review of a multifactorial probability based model (Lindor 2012) that included a statistical weighting of segregation analysis, co-occurrence in trans, pathological profiles, personal and family history of cancer showed that, for this variant, odds in favor of causality was 1.02x10-3 and posterior probability of being deleterious was 2.08x10-5. Authors classify the variant as IARC Class 1 (Least Likely to be pathogenic) variant. Five ClinVar submissions including an expert panel (evaluation after 2014) cite the variant twice as benign and three times as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000083108	SCV001139091	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000167796	SCV001148984	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BS3:Supporting
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000167796	SCV002010365	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163006	SCV002533882	likely benign	Hereditary cancer-predisposing syndrome	2021-08-03	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000044444	SCV002550336	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083108	SCV000115182	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083108	SCV000146451	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735551	SCV000863689	uncertain significance	Breast and/or ovarian cancer	2003-02-07	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000044444	SCV001906165	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000044444	SCV001974656	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000044444	SCV001979415	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537194	SCV004710778	benign	BRCA2-related disorder	2022-02-11	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).