ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.389_391delinsTCT (p.Tyr130_Arg131delinsPheTer) (rs1064793054)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561776 SCV000665913 pathogenic Hereditary cancer-predisposing syndrome 2017-03-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000485955 SCV000564716 pathogenic not provided 2016-12-08 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.389_391delACAinsTCT at the cDNA level and p.Tyr130PhefsX2(Y130FfsX2) at the protein level. This variant could also be described as BRCA1 Tyr130_Arg131delinsPheTer(Y130_R131delinsFX), as well as BRCA1 508_510delACAinsTCT using alternate nomenclature. The normalsequence, with the bases that are deleted and inserted in brackets, is GGCT[delACA][insTCT]GAAA. This deletion andinsertion results in the replacement of adjacent Tyrosine and Arginine residues with a Phenylalanine residue and apremature stop codon, and is predicted to cause loss of normal protein function through either protein truncation ornonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it isconsidered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000779894 SCV000916787 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-30 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.389_391delinsTCT (p.Tyr130_Arg131delinsPheX) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.E143*, p.E149*, and p.Q155*). The variant was absent in 246248 control chromosomes (gnomAD). To our knowledge, no occurrence of c.389_391delinsTCT as a single variant in individuals affected with Hereditary Breast and Ovarian Cancer has been reported, but p.Y130F and p.R131X have been reported in two affected unrelated individuals (BIC database). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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