ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4570T>G (p.Phe1524Val) (rs56386506)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163006 SCV000213494 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083108 SCV000146451 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000163006 SCV000537475 likely benign Hereditary cancer-predisposing syndrome 2015-04-28 criteria provided, single submitter clinical testing
Counsyl RCV000083108 SCV000488400 benign Breast-ovarian cancer, familial 2 2016-03-17 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000083108 SCV000244449 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000208
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735551 SCV000863689 uncertain significance Breast and/or ovarian cancer 2003-02-07 no assertion criteria provided clinical testing
GeneDx RCV000044444 SCV000210606 likely benign not specified 2017-11-14 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.
Integrated Genetics/Laboratory Corporation of America RCV000044444 SCV000694782 likely benign not specified 2017-11-03 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4570T>G (p.Phe1524Val) variant involves the alteration of a conserved nucleotide that leads to the alteration of the first, highly conserved amino acid position in the FxxA motif of the BRC4 domain that participates in the binding of Rad51 (Scott 2016). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index), however, these predictions have not been confirmed by functional studies. This variant was found in 7/276512 control chromosomes at a frequency of 0.0000253, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant is reported in several HBOC patients (Caux-Moncoutier 2009, Haffty 2009, Meyer 2003, Meyer 2012), however due to the lack of primary data relating to co-segregation and co-occurrence analysis, these data cannot be used as evidence of pathogenicity for the variant. A review of a multifactorial probability based model (Lindor 2012) that included a statistical weighting of segregation analysis, co-occurrence in trans, pathological profiles, personal and family history of cancer showed that, for this variant, odds in favor of causality was 1.02x10-3 and posterior probability of being deleterious was 2.08x10-5. Authors classify the variant as IARC Class 1 (Least Likely to be pathogenic) variant. Multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign" or "benign", however without providing information to independently evaluate. Taken together, due to lack of clinical information and absence of functional studies, this variant is classified as a Likely Benign, until more evidence becomes available.
Invitae RCV000167796 SCV000072457 likely benign Hereditary breast and ovarian cancer syndrome 2017-12-13 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083108 SCV000115182 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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