ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.83_88GCGCCG[2] (p.28_29GA[2]) (rs397507458)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587891 SCV000057176 likely benign not provided 2018-04-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000544255 SCV000659082 uncertain significance Rasopathy 2019-07-30 criteria provided, single submitter clinical testing This variant, c.95_100delGCGCCG, results in the deletion of 2 amino acids of the BRAF protein (p.Gly32_Ala33del), but otherwise preserves the integrity of the reading frame. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with BRAF-related disease. ClinVar contains an entry for this variant (Variation ID: 40338). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids 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.
Integrated Genetics/Laboratory Corporation of America RCV000587891 SCV000698349 uncertain significance not provided 2016-07-18 criteria provided, single submitter clinical testing Variant summary: The BRAF c.95_100delGCGCCG (p.Gly32_Ala33del) variant results in the deletion of a Gly and Ala in a stretch of Gly-Ala repeats. One in silico tool predicts a benign outcome for this variant. This variant is absent in 10568 control chromosomes. The variant has been cited in one tumor, but it is unclear if this was a germline or somatic variant and no other details were provided (Cheng_JMD_2015). In addition, one clinical diagnostic laboratory classified this variant as a VUS. Because of the limited clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Laboratory for Molecular Medicine, Partners HealthCare 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,; dbSNP r s397515331).
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000853029 SCV000995786 likely benign Dilated cardiomyopathy 2019-05-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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