ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.722C>T (p.Thr241Met) (rs387906660)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000033281 SCV000927841 pathogenic not provided 2018-08-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515432 SCV000611252 pathogenic Cardiofaciocutaneous syndrome 1; Lung cancer; Noonan syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000033281 SCV000057186 pathogenic not provided 2019-01-14 criteria provided, single submitter clinical testing The T241M pathogenic variant in the BRAF gene has been reported as de novo in an individual with a clinical diagnosis of Noonan syndrome (Sarkozy et al., 2009). Additionally, it has been confirmed de novo in a patient with features of a RASopathy at GeneDx. Other missense variants at the same codon (T241R and T241P) have been reported in association with Noonan syndrome and NSML/Costello syndrome, respectively (Sarkozy et al., 2009; Nava et al., 2007), and missense variants in nearby residues (T244P, L245F, A246P) have been reported in the Human Gene Mutation Database in association with cardio-facio-cutaneous syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The T241M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T241M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.
GeneReviews RCV000208540 SCV000264341 pathogenic Noonan syndrome 1 2016-02-25 no assertion criteria provided literature only
Invitae RCV000545320 SCV000659079 pathogenic Rasopathy 2017-08-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 241 of the BRAF protein (p.Thr241Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with Noonan Syndrome (PMID: 19206169). ClinVar contains an entry for this variant (Variation ID: 29805). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Thr241Pro) has been determined to be pathogenic in individuals affected with Cardio-facio-cutaneous (CFC) syndrome (PMID: 17704260, 18042262, 23950000). This suggests that the threonine residue is critical for BRAF protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211753 SCV000061620 pathogenic Noonan syndrome 2017-11-02 criteria provided, single submitter clinical testing The p.Thr241Met variant in BRAF has been previously reported in 3 individuals wi th clinical features of Noonan syndrome, including 2 de novo occurrences (LMM da ta, Sarkozy 2009, ClinVar Variation ID 29805). It has also been identified in 1/ 124756 European chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs387906660). Furthermore, 3 other missense vari ants at position p.241 (p.Thr241Arg, p.Thr241Pro, p.Thr241Lys) have been identif ied in individuals with clinical features of Noonan syndrome, Cardio-facio-cutan eous syndrome, LEOPARD, or Costello syndrome (Sarkozy 2009, LMM data), suggestin g that changes at this position are not tolerated. In summary, the p.Thr241Met v ariant meets criteria to be classified as pathogenic for Noonan syndrome in an a utosomal dominant manner. ACMG/AMP Criteria applied: PM5_Strong; PM6_Strong; PM2 ; PP2.
OMIM RCV000022678 SCV000043967 pathogenic Noonan syndrome 7 2009-04-01 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000022678 SCV000803610 likely pathogenic Noonan syndrome 7 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Noonan syndrome 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:19206169). PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

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