Submissions for variant NM_000059.4(BRCA2):c.1964C>G (p.Pro655Arg)

gnomAD frequency: 0.00054  dbSNP: rs28897712

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113003	SCV000244428	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 = 0.0000686
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043931	SCV000071944	benign	Hereditary breast ovarian cancer syndrome	2025-02-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000113003	SCV000154034	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only
GeneDx	RCV000168555	SCV000167339	benign	not specified	2013-10-03	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	RCV000162572	SCV000212988	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735527	SCV000219313	benign	Breast and/or ovarian cancer	2021-06-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000168555	SCV000225171	likely benign	not specified	2014-11-07	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000043931	SCV000296851	likely benign	Hereditary breast ovarian cancer syndrome	2015-09-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113003	SCV000383646	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-01	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000168555	SCV000593707	benign	not specified	2016-12-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000168555	SCV000602834	benign	not specified	2018-07-20	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162572	SCV000679710	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162572	SCV000683465	benign	Hereditary cancer-predisposing syndrome	2015-04-15	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113003	SCV000744423	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000168555	SCV000805661	benign	not specified	2016-07-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000113003	SCV001139020	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162572	SCV002533284	benign	Hereditary cancer-predisposing syndrome	2020-03-20	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000034434	SCV002563160	benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS1, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168555	SCV002761150	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002482931	SCV002801750	likely benign	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	2021-11-24	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000043931	SCV002819187	benign	Hereditary breast ovarian cancer syndrome	2022-09-08	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000113003	SCV000043201	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-03	no assertion criteria provided	research	BS1 based on allele frequency in AJ population of 0.002115 in gnomAD. BP4 based on REVEL score of 0.150. PMID:15290653 provides evidence for co-occurrence with pathogenic variants and lack of segregation, BP5.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113003	SCV000145988	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000168555	SCV000591785	benign	not specified		no assertion criteria provided	clinical testing	The p.Pro655Arg variant has been reported in the literature in 2 of 600 proband chromosomes of individuals with hereditary breast cancer and ovarian cancer, although no control chromosomes were tested to establish the frequency in the general population (Goldgar 2004, Frank 2002, Biswas 2012, Walsh 2006, Caux-Moncoutier 2009). Frank et al (2008) described the prevalence of this variant at >5% of the Ashkenazi Jewish population, supporting the likelihood that this variant has “little clinical consequence”. The p.Pro655 residue is not highly conserved in mammals; however, computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. The variant is listed in the dbSNP database (ID#: rs28897712) with a minor allele frequency of <0.003. Functional studies including protein structure prediction, detection of full-length protein and sensitivity to DNA damaging reagents, predict this variant to be "non-pathogenic" (Biswas 2012). In the UMD database, this variant is considered to have “neutral” biological significance. The UMD database has also reported this variant in one individual (out of 8) with breast or ovarian cancer, where a second pathogenic BRCA2 mutation was also detected, and in another individual where a pathogenic BRCA1 mutation was also detected, further suggesting that this is a benign variant. This variant has been reported 142 times in the BIC database. The exome variant server has reported this variant in 10/13006 normal chromosomes. In summary, based on the above information, this variant is classified as Benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000034434	SCV000778651	likely benign	not provided	2016-11-29	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162572	SCV000787922	benign	Hereditary cancer-predisposing syndrome	2018-09-06	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735527	SCV000863665	benign	Breast and/or ovarian cancer	2012-08-30	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000168555	SCV001905707	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000168555	SCV001931493	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000168555	SCV001953047	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000168555	SCV002036316	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000113003	SCV004244241	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing