Submissions for variant NM_000059.4(BRCA2):c.2127G>C (p.Leu709=)

gnomAD frequency: 0.00001  dbSNP: rs554040246

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495711	SCV000578025	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 0.0013 (East Asian), derived from ExAC (2014-12-17).
Ambry Genetics	RCV000164090	SCV000214701	likely benign	Hereditary cancer-predisposing syndrome	2014-09-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV001082804	SCV000252605	benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240769	SCV000265951	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000164090	SCV000683468	likely benign	Hereditary cancer-predisposing syndrome	2016-05-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000495711	SCV000786148	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000195970	SCV001133700	benign	not provided	2018-12-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000495711	SCV001139021	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501646	SCV001362880	benign	not specified	2019-02-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2127G>C alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.9e-05 in 245968 control chromosomes, predominantly at a frequency of 0.00099 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.32 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant has been described in several sequencing studies in patients of Eastern Asian origin consistent with the occurrences seen in the gnomAD database. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, four of whom classified the variant as benign (n=4)/likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000195970	SCV001890594	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164090	SCV002533295	likely benign	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353815	SCV000591790	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Leu709Leu 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.The p.Leu709Leu variant was identified in the literature in 3 of 3330 proband chromosomes (frequency: 0.001) from individuals with breast cancer and was not identified in 972 control chromosomes from these studies (Kim 2006, Suter 2004). The variant was not identified in any databases searched, including: dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, LOVD, COSMIC, ClinVar, GeneInsight VariantWire, BIC, and UMD. 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 predicted benign.