Submissions for variant NM_000059.4(BRCA2):c.6921A>G (p.Ser2307=)

gnomAD frequency: 0.00019  dbSNP: rs181183366

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000409129	SCV000579101	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
GeneDx	RCV000160238	SCV000210639	benign	not specified	2014-09-19	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	RCV000163368	SCV000213906	likely benign	Hereditary cancer-predisposing syndrome	2014-10-14	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196553	SCV000253032	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000196553	SCV000383750	likely benign	Hereditary breast ovarian cancer syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000377750	SCV000383751	likely benign	Fanconi anemia	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000409129	SCV000489320	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163368	SCV000683827	likely benign	Hereditary cancer-predisposing syndrome	2016-04-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589859	SCV000695007	likely benign	not provided	2017-04-24	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.6921A>G (p.Ser2307Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2/116362 control chromosomes at a frequency of 0.0000172, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in a BrC patient without strong evidence for causality. In addition, five out of 6 clinical diagnostic laboratories/reputable databases classified this variant as likely benign and one lab classified it as benign, all without evidence for independent evaluation. Taken together, this variant is classified as Likely Benign.
PreventionGenetics, part of Exact Sciences	RCV000589859	SCV000805752	likely benign	not provided	2017-08-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589859	SCV000883496	likely benign	not provided	2018-01-16	criteria provided, single submitter	clinical testing	The BRCA2 c.6921A>G; p.Ser2307Ser variant (rs181183366) is reported in the medical literature in an individual with breast cancer (Borg 2010), but is also reported as benign or likely benign in the ClinVar database (Variation ID: 182293). The variant is listed in the Genome Aggregation Database in 15 out of 276360 alleles. This is a silent variant, the nucleotide at this position is weakly conserved across species, and computational algorithms predict this variant does not alter mRNA splicing. Considering available information, this variant is classified as likely benign. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160238	SCV000889114	benign	not specified	2022-03-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000160238	SCV002070136	likely benign	not specified	2020-04-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163368	SCV002536280	likely benign	Hereditary cancer-predisposing syndrome	2020-11-04	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354273	SCV001548847	likely benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	The BRCA2 p.Ser2307 was identified in 1 of 4206 proband chromosomes (freq: 0.0002) from individuals with breast cancer (Borg 2010). The variant was identified in dbSNP (rs181183366) as “with other allele”, ClinVar (classified as likely benign by Invitae, Ambry Genetics, Color, Counsyl and 7 other submitters; and as benign by GeneDx), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 2x). The variant was identified in control databases in 15 of 281,468 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 15 of 24,546 chromosomes (freq: 0.0006); it was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, European, Other or South Asian populations. The p.Ser2307= 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. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000589859	SCV001800092	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589859	SCV001967756	likely benign	not provided		no assertion criteria provided	clinical testing