Submissions for variant NM_000059.4(BRCA2):c.4071A>C (p.Leu1357=)

gnomAD frequency: 0.00059  dbSNP: rs140556653

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000211027	SCV000578009	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 0.0017 (African), derived from ExAC (2014-12-17).
GeneDx	RCV000173967	SCV000167361	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000211027	SCV000195980	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163239	SCV000213766	likely benign	Hereditary cancer-predisposing syndrome	2014-06-10	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.
Eurofins Ntd Llc (ga)	RCV000173967	SCV000225163	likely benign	not specified	2015-04-20	criteria provided, single submitter	clinical testing
Invitae	RCV001084963	SCV000252607	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000472272	SCV000541056	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163239	SCV000683600	likely benign	Hereditary cancer-predisposing syndrome	2015-09-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588664	SCV000694740	benign	not provided	2016-08-23	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.4071A>C (p.Leu1357Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation Taster predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 18/120766 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0017599 (18/10228). This frequency is about 2.35 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant was reported in BrC patients without strong evidence for causality. In addition, several clinical diagnostic laboratories have classified this variant as likely benign/benign. It was also found to co-occur with a deleterious variant BRCA2 c. c.5351dup in one sample (UMD). Taken together, this variant is classified as Benign.
Genetic Services Laboratory, University of Chicago	RCV000173967	SCV002068659	likely benign	not specified	2021-07-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163239	SCV002533845	likely benign	Hereditary cancer-predisposing syndrome	2020-12-18	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001084963	SCV004014960	benign	Hereditary breast ovarian cancer syndrome	2023-04-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353951	SCV000591888	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Leu1357Leu variant was identified in 6 of 918 proband chromosomes (frequency: 0.007) from individuals or families of Nigerian descent with Breast Cancers), and was not determined in 148 control chromosomes from healthy individuals (Fackenthal 2012, Fackenthal 2005).The variant was previously identified by our laboratory in 1 individual of Black/ African descent with Breast Cancer. The variant was also identified in dbSNP (ID: rs140556653 “With benign allele”, with a minor allele frequency of 0.0006(1000 Genomes Project);in NHLBI Exome Sequencing Project (Exome Variant Server)in 10 of 4406 African Americans and 0 of 8596 European chromosomes; In Exome Aggregation Consortium (ExAC) database it was identified in 18 of 10228 Africans and not found in European (Non-Finnish), East Asian, Latino, South Asian, European (Finnish) or Other individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin.The variant was also identified in ClinVar database (classified as benign by GeneDX and as likely benign by Ambry genetics) and UMD (1X as a 3 unvalidated variant).The variant was not identified in COSMIC, LOVD, GeneInsight through the Canadian Open Genetics Repository and the BIC database The p.Leu1357Leu 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 p.Leu1357Leu variant occurs outside of the splicing consensus sequence and 5 in silico or computational prediction software programs(SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a greater than 10% difference in splicing although this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.