ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1127T>G (p.Phe376Cys) (rs80358410)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203669 SCV000071755 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 376 of the BRCA2 protein (p.Phe376Cys). The phenylalanine residue is weakly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51068). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000130007 SCV000184832 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000043742 SCV000210263 likely benign not specified 2016-08-16 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.
Counsyl RCV000112882 SCV000488358 uncertain significance Breast-ovarian cancer, familial 2 2016-03-08 criteria provided, single submitter clinical testing
Color RCV000130007 SCV000683402 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000043742 SCV000918925 uncertain significance not specified 2018-06-11 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1127T>G (p.Phe376Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two out of five predict the variant creates a 5 prime donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 120780 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1127T>G has been reported in individuals affected with Hereditary Breast and Ovarian Cancer (NHGRI BIC database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four labs classified it as VUS and one lab classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000112882 SCV000145818 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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