ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1395A>C (p.Val465=) (rs11571641)

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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) RCV000112916 SCV000579057 likely benign Breast-ovarian cancer, familial 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/).
Invitae RCV000043797 SCV000071810 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000173627 SCV000167333 benign not specified 2014-03-11 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 RCV000162500 SCV000212888 likely benign Hereditary cancer-predisposing syndrome 2014-08-13 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 RCV000112916 SCV000220253 likely benign Breast-ovarian cancer, familial 2 2014-04-17 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000173627 SCV000224754 likely benign not specified 2014-07-21 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000112916 SCV000267745 benign Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000043797 SCV000576433 likely benign Hereditary breast and ovarian cancer syndrome 2017-02-14 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000173627 SCV000586928 benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162500 SCV000683421 benign Hereditary cancer-predisposing syndrome 2015-04-22 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000112916 SCV000743260 likely benign Breast-ovarian cancer, familial 2 2017-07-31 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000112916 SCV000744411 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282502 SCV000883472 benign none provided 2020-02-24 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000755857 SCV001148974 likely benign not provided 2019-03-01 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000112916 SCV000145864 uncertain significance Breast-ovarian cancer, familial 2 1999-12-30 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000173627 SCV000591742 benign not specified no assertion criteria provided clinical testing The BRCA2 p.Val465Val 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 the abolishment of an existing splice site or the creation of a new splice site, and a splicing minigene assay found the variant did not have an effect on splicing (Théry 2011). The variant was identified in the literature in 2 of 8048 proband chromosomes from individuals or families with breast or ovarian cancer; however control chromosomes were not evaluated in this study thus the prevalence of the variant in the general population could not be determined (van der Hout 2006). Another variant with the same synonymous amino acid change but a different nucleotide change (c.1395A>T) was identified in one individual with breast cancer in a study by Evans (2008); however, control chromosomes were not included in this study. The p.Val465Val variant was identified in the NIH Polymorphism Discovery Resource (NIHPDR) PDR90 cohort in 1 of 180 chromosomes (frequency: 0.006), and in the Exome Variant Server Exome Sequencing Project in 4 of 13006 European American alleles (frequency 0.0003), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in dbSNP (ID: rs11571641) “With uncertain allele”, HGMD, LOVD, the ClinVar database (classified as benign by Invitae and GeneDx), the BIC database (1X with unknown clinical importance), and UMD (25X as a neutral variant). In UMD the variant was identified with three different co-occurring pathogenic BRCA2 variants and one pathogenic BRCA1 variant, increasing the likelihood that the p.Val465Val variant does not have clinical significance. Furthermore, Myriad classifies this as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000112916 SCV000733230 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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