Submissions for variant NM_000059.4(BRCA2):c.8503T>C (p.Ser2835Pro)

gnomAD frequency: 0.00202  dbSNP: rs11571746

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113950	SCV001161621	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	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 = 0.000863
Invitae	RCV000167840	SCV000073553	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000113950	SCV000154089	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-03-20	criteria provided, single submitter	literature only
GeneDx	RCV000120364	SCV000167411	benign	not specified	2014-01-28	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	RCV000129146	SCV000183867	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.
Pathway Genomics	RCV000113950	SCV000223756	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120364	SCV000227606	benign	not specified	2015-12-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113950	SCV000383785	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-06	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167840	SCV000494354	benign	Hereditary breast ovarian cancer syndrome	2014-09-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120364	SCV000538476	likely benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.7% (77/10388) African chromosomes
Color Diagnostics, LLC DBA Color Health	RCV000129146	SCV000683973	likely benign	Hereditary cancer-predisposing syndrome	2015-04-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656624	SCV000885095	likely benign	not provided	2023-03-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000113950	SCV001139219	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001110062	SCV001267451	likely benign	Fanconi anemia complementation group D1	2018-03-06	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000656624	SCV001371333	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	BRCA2: BP4
Genetic Services Laboratory, University of Chicago	RCV000120364	SCV002068922	likely benign	not specified	2022-01-04	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000167840	SCV002515155	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000129146	SCV002531953	benign	Hereditary cancer-predisposing syndrome	2020-10-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120364	SCV002551826	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483047	SCV002798772	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	2022-02-07	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000113950	SCV004016859	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735612	SCV004240366	benign	Breast and/or ovarian cancer	2022-08-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000113950	SCV004846027	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
ITMI	RCV000120364	SCV000084516	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113950	SCV000147386	benign	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	RCV000113950	SCV000592204	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The p.Ser2835Pro variant has been identified in 7 out of 7570 proband chromosomes (frequency 0.001) in individuals with cutaneous malignant melanoma, and breast and ovarian cancer phenotypes, and identified in 1 out of 5064 control chromosomes (frequency <0.001) (Casula 2006, Caux-Moncoutier 2011, Frackenthal 2012, Johnson 2007, Palomba 2009, Tazzite 2012, Malone 2000, Karchin 2008, Schoumacher 2001). It is listed in dbSNP database as coming from a “clinical source” (ID#: rs11571746) however no frequency information was provided. The variant is identified in the EVS server as a low frequency variant increasing the likelihood this variant does not have clinical significance. The p.Ser2835 is not conserved in mammals, and computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein, and the variant amino acid Proline (Pro) residue is present in cat, dog and zebrafish, suggesting this variant may not be functionally important. In the UMD database, this variant has been identified in 2 (out of 13) individuals with breast or ovarian cancers, where a second pathogenic BRCA1 mutation was also detected, further suggesting that this is a benign variant. In addition, it is presented 34 times in the BIC database as a variant with no clinical significance. In summary based on the information presented above this variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656624	SCV000778719	likely benign	not provided	2018-02-05	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735612	SCV000863750	benign	Breast and/or ovarian cancer	2013-04-13	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120364	SCV001905689	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120364	SCV001952953	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000120364	SCV001967551	benign	not specified		no assertion criteria provided	clinical testing