Submissions for variant NM_004333.6(BRAF):c.1056T>A (p.Asp352Glu)

dbSNP: rs1398817791

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001162453	SCV001324406	uncertain significance	LEOPARD syndrome 3	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001164494	SCV001326626	uncertain significance	Noonan syndrome 7	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Molecular Genetics, Royal Melbourne Hospital	RCV003994225	SCV004812363	uncertain significance	Noonan syndrome	2023-06-06	criteria provided, single submitter	clinical testing	This sequence change in BRAF is predicted to replace aspartic acid with glutamic acid at codon 352, p.(Asp352Glu). The aspartic acid residue is highly conserved (97 vertebrates, UCSC), and is not located in an annotated domain. There is a small physicochemical difference between aspartic acid and glutamic acid. BRAF, in which the variant was identified, is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PMID: 29493581). This variant is present in a single individual from the European (non-Finnish) population in the population database gnomAD v2.1 (1/113,738 alleles). To our knowledge, this variant has not been previously reported in the relevant scientific literature. It has been identified in an ostensibly healthy individual in ClinVar (ID: 910577). Computational evidence is uninformative for the missense substitution (REVEL = 0.407). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP2.