ClinVar Miner

Submissions for variant NM_001374258.1(BRAF):c.1511G>A (p.Gly504Glu) (rs121913348)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000033304 SCV001335316 pathogenic Rasopathy 2020-03-09 reviewed by expert panel curation The c.1391G>A (p.Gly464Glu) variant in BRAF has been observed in 2 probands with phenotypes consistent with cardiofaciocutaneous syndrome (PS4_Supporting; LMM internal data, SCV000197160.4; GeneDx internal data, SCV000057209.13). One of these cases was de novo with maternity and paternity confirmed, while the other was de novo without confirmation of maternity or paternity (PS2, PM6). The p.Gly464Glu variant was absent from large population studies (PM2; gnomad.broadinstitute.org). In vitro functional assays indicate that this variant may impact protein function (PS3; PMID: 25155755). It occurs in the P-loop domain of the protein, which has been identified as an important region for protein function (PM1; 29493581). Computational prediction tools and conservation analyses also suggest that this variant may impact the protein (PP3). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP criteria applied: PS2, PS3, PS4_Supporting, PM1, PM2, PM6, PP2, PP3.
GeneDx RCV000207512 SCV000057209 pathogenic not provided 2015-10-30 criteria provided, single submitter clinical testing The G464E missense mutation has not been reported as a mutation, but neither has it been published as a benign polymorphism. The position at which this mutation occurs is highly conserved across species and other missense mutations at this position (G464V, G464R) have been previously reported in the literature (Rodriguez-Viciana et al., 2008, Cave et al., 2008).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844618 SCV000197160 likely pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2018-02-15 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000207512 SCV000263062 likely pathogenic not provided 2015-07-23 criteria provided, single submitter clinical testing
Invitae RCV000033304 SCV000943342 uncertain significance Rasopathy 2018-08-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 464 of the BRAF protein (p.Gly464Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a BRAF-related disease. ClinVar contains an entry for this variant (Variation ID: 13964). Experimental studies have shown that this missense change disrupts BRAF inhibition, resulting in a constitutively active protein (PMID: 23680146, 25155755). Variants that disrupt the Gly464 amino acid residue in BRAF have been observed in affected individuals (PMID: 18413255, 18039235, 21062266, 19376813, 23680146). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.
OMIM RCV000014997 SCV000035253 pathogenic Carcinoma of colon 2003-08-15 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436895 SCV000505050 likely pathogenic Chronic lymphocytic leukemia 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418719 SCV000505051 likely pathogenic Neoplasm 2016-05-13 no assertion criteria provided literature only
Service de Génétique Moléculaire,Hôpital Robert Debré RCV001261044 SCV001438445 uncertain significance Cardio-facio-cutaneous syndrome no assertion criteria provided clinical testing

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