ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2538A>C (p.Ser846=) (rs11571654)

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Total submissions: 20
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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) RCV000113057 SCV000578016 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 0.0049 (South Asian), derived from ExAC (2014-12-17).
Invitae RCV000167797 SCV000072024 benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000044011 SCV000167345 benign not specified 2014-02-12 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 RCV000162905 SCV000213392 likely benign Hereditary cancer-predisposing syndrome 2014-08-11 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.
Counsyl RCV000113057 SCV000220710 likely benign Breast-ovarian cancer, familial 2 2014-09-19 criteria provided, single submitter literature only
Illumina Clinical Services Laboratory,Illumina RCV000113057 SCV000383653 likely benign Breast-ovarian cancer, familial 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000378892 SCV000383654 likely benign Fanconi anemia, complementation group D1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000167797 SCV000494432 benign Hereditary breast and ovarian cancer syndrome 2015-08-24 criteria provided, single submitter clinical testing Variant Summary: The variant of interest causes a synonymous change involving a non-conserved nucleotide with Mutation Taster predicting the variant to be a "polymorphism." 3/5 in silico programs via Alamut predict no significant effect on splicing and the removal of an ESE binding site, SRp40, although these predictions have yet to be functionally assessed. The variant of interest was observed in a large, broad control population, ExAC with an allele frequency of 98/120626 (1/1231, including 2 homozygotes), which exceeds the maximum expected allele frequency for a BRCA2 variant of 1/1333. The variant of interest has been reported in affected individuals via publications, including a reported co-occurrence with another pathogenic BRCA1 variant (5404delG; De Silva et al 2001). In addition, multiple reputable databases/clinical laboratories (BIC, GeneDx, Ambry Genetics, and Invitae) cite the variant with a classification of "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as benign.
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000044011 SCV000586935 benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162905 SCV000683490 benign Hereditary cancer-predisposing syndrome 2015-12-28 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000113057 SCV000743274 benign Breast-ovarian cancer, familial 2 2014-10-10 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000113057 SCV000744427 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000044011 SCV000805674 benign not specified 2017-05-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000044011 SCV001159041 benign not specified 2018-10-16 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113057 SCV000146064 benign Breast-ovarian cancer, familial 2 2010-10-28 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353445 SCV000591809 benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Ser846Ser 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. Two of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this is not very predictive of pathogenicity. The variant was identified in 5 of 5234 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Alsop 2012, Caux-Moncoutier 2011, Soumittra 2009); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs11571654) “With Benign, untested allele”, BIC (1X with no clinical importance), the ClinVar database (classified as benign by BIC and GeneDx; classification not provided by Invitae), and UMD (11X as an unclassified variant). The variant was identified in the 1000 Genomes Project in 5 chromosomes (frequency: 0.001), HAPMAP-GIH in 2 of 176 chromosomes (frequency: 0.011), Exome Variant Server ESP project in 2 of 8598 European American alleles. The variant was identified in several populations in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014), with the following allele counts and frequencies: South Asian (82/16468 alleles, frequency: 0.005), Latino (7/11470 alleles, frequency: 0.0006), European (Non-Finnish) (8/66348 alleles, frequency; 0.0001, and “Other” (1/904 alleles, frequency: 0.001). Notably two of the individuals tested in the ExAC database were homozygous for the variant (one South Asian and one Latino), increasing the likelihood that this variant may not have clinical significance. In addition, Myriad classifies this as a polymorphism (personal communication). In summary, based on the above information, this variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000656592 SCV000778653 likely benign not provided 2017-04-07 no assertion criteria provided clinical testing
True Health Diagnostics RCV000162905 SCV000805239 likely benign Hereditary cancer-predisposing syndrome 2018-05-09 no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000656592 SCV001905727 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000656592 SCV001952208 likely benign not provided no assertion criteria provided clinical testing

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