Submissions for variant NM_000059.4(BRCA2):c.3420T>C (p.Ser1140=)

gnomAD frequency: 0.00008  dbSNP: rs118093942

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)	RCV000113175	SCV000578021	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0036 (East Asian), derived from ExAC (2014-12-17).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082661	SCV000072203	benign	Hereditary breast ovarian cancer syndrome	2024-01-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000113175	SCV000154096	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-04-04	criteria provided, single submitter	literature only
GeneDx	RCV000123963	SCV000167355	benign	not specified	2014-03-14	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	RCV000162907	SCV000213394	likely benign	Hereditary cancer-predisposing syndrome	2014-08-05	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113175	SCV000267758	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000113175	SCV000575745	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162907	SCV000683555	benign	Hereditary cancer-predisposing syndrome	2016-05-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757044	SCV000885116	benign	not provided	2017-09-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770717	SCV000902195	benign	Breast and/or ovarian cancer	2017-07-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000757044	SCV001501466	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BP7
Genetic Services Laboratory, University of Chicago	RCV000123963	SCV002071819	benign	not specified	2021-08-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000113175	SCV004845155	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113175	SCV000146230	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-18	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354013	SCV000591860	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ser1140= variant was identified in 7 of 8452 proband chromosomes (frequency: 0.0008) from individuals or families with hereditary breast and ovarian cancer, and is classified as a benign polymorphism (Borg 2010, Dong_2015, Hu 2003, Kawahara 2004, Kim 2006, Suter 2004, Thirthagiri 2008). The variant was also identified in dbSNP (ID: rs118093942) as “With other allele”, ClinVar (as benign, reviewed by expert panel), Clinvitae (5x), COGR (as likely benign), LOVD 3.0 (4x), and UMD-LSDB (2x as "uncertain significance"). The variant was not identified in Cosmic, MutDB, BIC Database, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 76 of 276744 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 76 of 18862 chromosomes (freq: 0.004), while the variant was not observed in the African, Other, Latino, European (Non-Finnish), Ashkenazi Jewish, Finnish, and South Asian populations. The p.Ser1140= 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 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000123963	SCV001905955	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000757044	SCV001968030	likely benign	not provided		no assertion criteria provided	clinical testing