Submissions for variant NM_004333.6(BRAF):c.2029G>A (p.Asp677Asn)

gnomAD frequency: 0.00001  dbSNP: rs886041260

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000363862	SCV000329579	uncertain significance	not provided	2016-05-24	criteria provided, single submitter	clinical testing	The D677N variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.D677N was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant inthese populations. The D677N variant is a semi-conservative amino acid substitution, which mayimpact secondary protein structure as these residues differ in some properties. Moreover, thissubstitution occurs at a position that is conserved across species. However, in silico analysis isinconsistent in its predictions as to whether or not the variant is damaging to the proteinstructure/function.Therefore, based on the currently available information, it is unclear whether this variant ispathogenic or rare benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731553	SCV001983577	uncertain significance	not specified	2021-09-23	criteria provided, single submitter	clinical testing	Variant summary: BRAF c.2029G>A (p.Asp677Asn) results in a conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251222 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2029G>A has been reported in one individual affected with Parkinsons disease (Lubbe_2016), but has not been reported in any individual affected with Cardiofaciocutaneous Syndrome. These data do not provide unequivocal conclusions about association of the variant with Cardiofaciocutaneous Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV003539873	SCV004353756	uncertain significance	RASopathy	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 677 of the BRAF protein (p.Asp677Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 32746448). ClinVar contains an entry for this variant (Variation ID: 279928). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRAF protein function with a negative predictive value of 80%. 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.