Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_004333.4(BRAF):c.1227A>G (p.Ser409=)

Curation History

CA135058

40360 (ClinVar)

Gene: BRAF

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: dd0b96ec-49ad-4f28-801a-b7b31c5fe734

Approved on: 2017-04-03

Published on: 2018-12-10

HGVS expressions

NM_004333.4:c.1227A>G

NM_004333.4(BRAF):c.1227A>G (p.Ser409=)

NC_000007.14:g.140783108T>C

CM000669.2:g.140783108T>C

NC_000007.13:g.140482908T>C

CM000669.1:g.140482908T>C

NC_000007.12:g.140129377T>C

NG_007873.3:g.146657A>G

NM_001354609.1:c.1227A>G

NM_004333.5:c.1227A>G

NR_148928.1:n.1532A>G

ENST00000288602.10:c.1227A>G

ENST00000496384.6:n.50A>G

ENST00000497784.1:n.1262A>G

Benign

BA1 BP4 BP5 BP7

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The filtering allele frequency of the c.1227A>G (p.Ser409=) variant in the BRAF gene is 0.313% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (233/66620 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additionally, this variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). The p.Ser409= variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM, EGL Genetics internal data; GTR ID's: 21766, 26957, 500060; SCV000057203.8; SCV000061570.5; SCV000112807.7). Computational prediction tools and conservation analysis suggest that the p.Ser409= variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied: BA1, BP7, BP5, BP4.

BA1

The allele frequency of the c.1227A>G (p.Ser409=) variant in the BRAF gene is 1.53% (101/6602) of European (Finnish) chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BA1).

BP4

Computational prediction tools and conservation analysis suggest that the p.Ser409= variant does not impact the protein (BP4).

BP5

The p.Ser409= variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM, EGL Genetics internal data; GTR ID's: 21766, 26957, 500060; SCV000057203.8; SCV000061570.5; SCV000112807.7).

BP7

Additionally, this variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7).

Curation History

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