ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6172T>A (p.Phe2058Ile) (rs80358857)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129210 SCV000183960 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000083124 SCV000146784 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000129210 SCV000683758 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing
GeneDx RCV000587108 SCV000210625 uncertain significance not provided 2018-01-04 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6172T>A at the cDNA level, p.Phe2058Ile (F2058I) at the protein level, and results in the change of a Phenylalanine to an Isoleucine (TTT>ATT). This variant, also published as BRCA2 6400T>A using alternate nomenclature, has been reported in at least one individual with breast cancer (Loughrey 2008). BRCA2 Phe2058Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Phe2058Ile is located in the BRC-8 domain and the RAD51 binding domain (Cole 2011, Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Phe2058Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587108 SCV000694945 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6172T>A (p.Phe2058Ile) variant, alternatively also known as 6400T>A, involves the alteration of a conserved nucleotide and is located in BRC-8 repeat region of the protein (UniProt). 5/5 in silico tools predict damaging outcome for this variant. This variant is absent in 120892 control chromosomes from ExAC. It has been reported in multiple HBOC patients/families or individuals undergoing BRCA1/2 testing in literature and clinical databases without strong evidence for or against pathogenicity. In ClinVar, while three submitters have classified this variant as uncertain significance, one submitter has classified it as likely benign. In one internal sample with this variant, another pathogenic variant has also been reported (MUTYH p.Gly396Asp), however, pathogenic variants in MUTYH gene have not been classically linked to HBOC. Multifactorial likelihood assessment shows that it is unlikely pathogenic (Whiley_2014). Taken together, this variant is currently classified as Variant of Unknown Significance (VUS).
Invitae RCV000044860 SCV000072873 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with isoleucine at codon 2058 of the BRCA2 protein (p.Phe2058Ile). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 52024). Based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a low probability of being pathogenic (PMID: 24489791). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212247 SCV000600682 uncertain significance not specified 2016-10-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587108 SCV000889086 uncertain significance not provided 2017-11-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083124 SCV000115198 likely benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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