Submissions for variant NM_004333.6(BRAF):c.83GCGCCG[2] (p.28GA[2])

dbSNP: rs397507458

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587891	SCV000057176	benign	not provided	2021-02-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25801821, 30826992, 32740981)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544255	SCV000659082	uncertain significance	RASopathy	2025-01-06	criteria provided, single submitter	clinical testing	This variant, c.95_100del, results in the deletion of 2 amino acid(s) of the BRAF protein (p.Gly32_Ala33del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397507459, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with BRAF-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000033271	SCV000731840	likely benign	not specified	2017-08-25	criteria provided, single submitter	clinical testing	p.Gly32_Ala33del in exon 1 of BRAF: This variant is not expected to have clinica l significance due to a lack of conservation across species, including mammals. Of note, despite high nearby amino acid conservation, >20 species have a deletio n of the glycine (Gly) and alanine (Ala) residues at positions 32 and 33. This d eletion has also been identified in 0.1% (11/14082) of African chromosomes by th e Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP r s397515331).
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000853029	SCV000995786	likely benign	Primary dilated cardiomyopathy	2019-05-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000033271	SCV001338969	likely benign	not specified	2020-03-16	criteria provided, single submitter	clinical testing	Variant summary: BRAF c.95_100delGCGCCG (p.Gly32_Ala33del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 0.00023 in 126314 control chromosomes (gnomAD, pass quality filter). The observed variant frequency is approximately 92 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRAF causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.95_100delGCGCCG in individuals affected with Noonan Syndrome and Related Conditions has been reported. However, it has been reported in patients with other type of cancer without conclusive evidence (Cheng_2015, Shen_2019). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=3, VUS n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000587891	SCV003828535	uncertain significance	not provided	2019-11-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003362666	SCV004070665	likely benign	Cardiovascular phenotype	2023-09-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000587891	SCV005074130	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	BRAF: PM4:Supporting, BS1
PreventionGenetics, part of Exact Sciences	RCV003904886	SCV004719495	likely benign	BRAF-related disorder	2023-02-06	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).