ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5268A>G (p.Val1756=)

gnomAD frequency: 0.00005  dbSNP: rs199879914
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Total submissions: 17
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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) RCV000495454 SCV000579046 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/).
Labcorp Genetics (formerly Invitae), Labcorp RCV000122915 SCV000166173 benign Hereditary breast ovarian cancer syndrome 2024-01-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162513 SCV000212905 likely benign Hereditary cancer-predisposing syndrome 2014-10-10 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.
Illumina Laboratory Services, Illumina RCV000495454 SCV000383712 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000329212 SCV000383713 uncertain significance Fanconi anemia complementation group D1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health RCV000162513 SCV000537427 likely benign Hereditary cancer-predisposing syndrome 2015-06-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV000456829 SCV000541031 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175341 SCV000694850 likely benign not specified 2019-01-21 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5268A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 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 7.2e-05 in 250366 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (7.2e-05 vs 0.00075), allowing no conclusion about variant significance. In addition, the variant was reported in 4/7325 European American women (i.e. with a frequency of 0.000546), who were older than 70 years of age, and never had cancer (in the FLOSSIES database). c.5268A>G has been reported in the literature in a validation study, although with limited information (i.e. lack of co-occurrence and cosegregation data); thus this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with another pathogenic variant have been reported (BRCA2 c.5946delT/p.Ser1982fsX22 in our internal database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (3 classifying it as Benign, 2 as Likely Benign, and 1 as a VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585978 SCV000887846 benign not provided 2023-07-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000495454 SCV001526956 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2018-03-22 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV000585978 SCV001869823 benign not provided 2015-03-03 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000162513 SCV002536118 likely benign Hereditary cancer-predisposing syndrome 2021-01-01 criteria provided, single submitter curation
CeGaT Center for Human Genetics Tuebingen RCV000585978 SCV004010220 likely benign not provided 2024-05-01 criteria provided, single submitter clinical testing BRCA2: BP4, BP7
True Health Diagnostics RCV000162513 SCV000886674 likely benign Hereditary cancer-predisposing syndrome 2018-09-06 no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000585978 SCV001905959 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000585978 SCV001959297 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000585978 SCV001978222 likely benign not provided no assertion criteria provided clinical testing

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