ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4071A>C (p.Leu1357=) (rs140556653)

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Total submissions: 10
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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 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 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000173967 SCV000225163 likely benign not specified 2015-04-20 criteria provided, single submitter clinical testing
Invitae RCV001084963 SCV000252607 benign Hereditary breast and ovarian cancer syndrome 2020-11-25 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 Health, Inc 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.
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.

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