Submissions for variant NM_000059.4(BRCA2):c.7242A>G (p.Ser2414=)

dbSNP: rs1799955

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113739	SCV000245107	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-01-12	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.3864 (Asian), 0.1585 (African), 0.219 (European), derived from 1000 genomes (2012-04-30).
Counsyl	RCV000113739	SCV000154042	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only	High frequency in a 1kG or ESP population: 21.3 %.
Ambry Genetics	RCV000130994	SCV000185917	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113739	SCV000196003	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000152882	SCV000202298	benign	not specified	2016-01-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000152882	SCV000301774	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113739	SCV000383762	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-13	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000394273	SCV000383763	benign	Fanconi anemia complementation group D1	2018-01-13	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000336026	SCV000494341	benign	Hereditary breast ovarian cancer syndrome	2013-12-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130994	SCV000537337	benign	Hereditary cancer-predisposing syndrome	2015-03-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000474663	SCV000541019	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000152882	SCV000586972	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656617	SCV000602741	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152882	SCV000605773	benign	not specified	2016-05-23	criteria provided, single submitter	clinical testing	p.Ser2414Ser in exon 14 of BRCA2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 38.47% (3323/8638) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs1799955).
GeneKor MSA	RCV000152882	SCV000693641	benign	not specified	2017-11-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113739	SCV000743330	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-10	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113739	SCV000744512	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV000336026	SCV001000323	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000336026	SCV002025813	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	RCV000113739	SCV002097619	benign	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000336026	SCV002515140	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000113739	SCV004016815	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113739	SCV000147060	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113739	SCV000189315	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000152882	SCV000592104	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 p.Ser2414Ser variant was identified globally in 609 of 3040 proband chromosomes (frequency: 0.200) from individuals or families with familial and sporadic breast cancer, and was present in 68 of 364 control chromosomes (frequency: 0.187) from healthy individuals (Akilzhanova 2013, Fackenthal 2012, Jalkh 2012, Toh 2008, Marchina 2010, Saxena 2006, Diez 2003). The variant was identified in dbSNP (ID: rs1799955) “With benign allele”, in the 1000 Genomes Project in 271 of 1165 chromosomes (frequency: 0.2326), HAPMAP-CEU in 22 of 116 chromosomes (frequency: 0.19), HAPMAP-YRI in 25 of 118 chromosomes (frequency: 0.212), HAPMAP-HCB in 29 of 90 chromosomes (frequency: 0.322), NHLBI Exome Sequencing Project (Exome Variant Server) in 1834 of 8600 European American alleles (frequency: 0.2132) and in 915 of 4600 African American alleles (frequency: 0.2077), and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 27219 (heterozygous) and 3228 (homozygous) of 121288 chromosomes (frequency: 0.2244) (or 3988 East Asian individuals, 1740 European(Finnish), 229 Other, 2430 African, 2263 Latino, 3954 South Asian, and 15843 European(Non-Finnish) individuals). The variant was also identified in the Clinvitae database (5X), LOVD, the ClinVar database (classified as a benign variant by multiple submitters with no conflicts; by the Sharing Clinical Reports Project, derived from Myriad reports, BIC, Emory Genetics, Ambry Genetics, GeneDx, and Counsyl), GeneInsight COGR database (1X, classified as “uncertain” by a clinical laboratory), the BIC database (183X with no clinical importance), and in UMD (7X classified as neutral and co-occuring with a pathogenic variant p.Lys82X). The p.Ser2414Ser variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000113739	SCV000733296	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656617	SCV000778705	benign	not provided	2016-11-29	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000152882	SCV001905713	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000152882	SCV001957132	benign	not specified		no assertion criteria provided	clinical testing