The c.1785T>G (p.Phe595Leu) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 19206169, 18042262; GTR ID's: 26957, 21766; ClinVar SCV000203922.4, SCV000207755.12). The variant has also been identified in at least 2 independent occurences in patients with clinical features of a RASopathy (PS4_Supporting; APHP-Robert Debré internal data; GTR ID 28338). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581, 16439621). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe595Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM2, PM1, PP2, PP3, PS4_Supporting.
ClinVar Genomic variation as it relates to human health
NM_004333.6(BRAF):c.1785T>G (p.Phe595Leu)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004333.6(BRAF):c.1785T>G (p.Phe595Leu)
Variation ID: 177672 Accession: VCV000177672.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q34 7: 140753350 (GRCh38) [ NCBI UCSC ] 7: 140453150 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 31, 2015 Feb 14, 2024 Apr 3, 2017 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004333.6:c.1785T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004324.2:p.Phe595Leu missense NM_001374258.1:c.1905T>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361187.1:p.Phe635Leu missense NM_001354609.2:c.1785T>G NP_001341538.1:p.Phe595Leu missense NM_001374244.1:c.1905T>G NP_001361173.1:p.Phe635Leu missense NM_001378467.1:c.1794T>G NP_001365396.1:p.Phe598Leu missense NM_001378468.1:c.1785T>G NP_001365397.1:p.Phe595Leu missense NM_001378469.1:c.1719T>G NP_001365398.1:p.Phe573Leu missense NM_001378470.1:c.1683T>G NP_001365399.1:p.Phe561Leu missense NM_001378471.1:c.1674T>G NP_001365400.1:p.Phe558Leu missense NM_001378472.1:c.1629T>G NP_001365401.1:p.Phe543Leu missense NM_001378473.1:c.1629T>G NP_001365402.1:p.Phe543Leu missense NM_001378474.1:c.1785T>G NP_001365403.1:p.Phe595Leu missense NM_001378475.1:c.1521T>G NP_001365404.1:p.Phe507Leu missense NC_000007.14:g.140753350A>C NC_000007.13:g.140453150A>C NG_007873.3:g.176415T>G LRG_299:g.176415T>G LRG_299t1:c.1785T>G P15056:p.Phe595Leu - Protein change
- F595L, F573L, F598L, F543L, F635L, F507L, F558L, F561L
- Other names
-
p.F595L:TTT>TTG
NM_004333.4(BRAF):c.1785T>G
- Canonical SPDI
- NC_000007.14:140753349:A:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BRAF | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1250 | 1364 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 4, 2021 | RCV000154266.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 15, 2021 | RCV000157825.7 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 13, 2016 | RCV000426478.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000445270.1 | |
| Pathogenic (3) |
reviewed by expert panel
|
Apr 3, 2017 | RCV000522002.7 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 03, 2017)
|
reviewed by expert panel
Method: curation
|
Noonan syndrome and Noonan-related syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen RASopathy Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000616396.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022 |
Comment:
The c.1785T>G (p.Phe595Leu) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features … (more)
The c.1785T>G (p.Phe595Leu) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 19206169, 18042262; GTR ID's: 26957, 21766; ClinVar SCV000203922.4, SCV000207755.12). The variant has also been identified in at least 2 independent occurences in patients with clinical features of a RASopathy (PS4_Supporting; APHP-Robert Debré internal data; GTR ID 28338). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581, 16439621). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe595Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM2, PM1, PP2, PP3, PS4_Supporting. (less)
|
|
|
Likely pathogenic
(Apr 01, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Cardio-facio-cutaneous syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000203922.4
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Comment:
The Phe595Leu variant in BRAF has been reported in the literature in one individ ual with clinical features of Cardio-facio-cutaneous syndrome (CFC; Rodriguez-Vi ciana 2006). … (more)
The Phe595Leu variant in BRAF has been reported in the literature in one individ ual with clinical features of Cardio-facio-cutaneous syndrome (CFC; Rodriguez-Vi ciana 2006). This same amino acid change caused by a different DNA change (c.178 5T>A) has also been reported to have occurred de novo in an individual with clin ical features of CFC syndrome (Schulz 2008). In addition, this variant was not i dentified in either parent of a proband (LMM unpublished data). Computational pr ediction tools and conservation analyses suggest that the Phe595Leu variant may impact the protein. In summary, this variant is likely pathogenic, though additi onal studies are required to fully establish its clinical significance. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Nov 04, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardio-facio-cutaneous syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002041673.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
Comment:
Variant summary: BRAF c.1785T>G (p.Phe595Leu) results in a non-conservative amino acid change located in the Protein Kinase Domain (IPR000719) of the encoded protein sequence. Four … (more)
Variant summary: BRAF c.1785T>G (p.Phe595Leu) results in a non-conservative amino acid change located in the Protein Kinase Domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251240 control chromosomes (gnomAD). c.1785T>G has been reported in the literature in multiple individuals affected with Cardiofaciocutaneous Syndrome (examples: Rodrigues-Viciana_2006, Sarkozy_2009, Yoon_2007, Pierpont_2010, Abe_2012, Alfieri_2013, Lee_2021). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Nov 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000207755.15
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect … (more)
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant has been reviewed and classified as pathogenic by the ClinGen RASopathy Expert Panel (Gelb et al., 2018); This variant is associated with the following publications: (PMID: 16439621, 18042262, 12068308, 32269299, 29752777, 33040082, 26582644, 30138938, 24957944, 15488754, 29493581, 15520807, 17603483, 23093928, 30977659, 32913992, 29084544, 19206169) (less)
|
|
|
Pathogenic
(May 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022614.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jul 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
RASopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004294693.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein … (more)
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt BRAF protein function. ClinVar contains an entry for this variant (Variation ID: 177672). This missense change has been observed in individual(s) with BRAF-related conditions (PMID: 16439621, 29084544, 33040082, 33318624). In at least one individual the variant was observed to be de novo. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 595 of the BRAF protein (p.Phe595Leu). (less)
|
|
|
Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
Melanoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000505586.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 13, 2016)
|
no assertion criteria provided
Method: literature only
|
Neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000505587.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
RASopathy
Affected status: yes, unknown
Allele origin:
unknown,
de novo
|
GenomeConnect - CFC International
Accession: SCV001245248.2
First in ClinVar: May 04, 2020 Last updated: Jan 08, 2022 |
Comment:
Variant was identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 05-19-2015 by lab or GTR ID GeneDx. Variant interpreted as Pathogenic … (more)
Variant was identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 05-19-2015 by lab or GTR ID GeneDx. Variant interpreted as Pathogenic and reported on 11-05-2020 by lab or GTR ID Mayo Clinic. GenomeConnect - CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Abnormality of eye movement (present) , Abnormal cardiovascular system morphology (present) , Feeding difficulties (present) , Abnormal intestine morphology (present) , Abnormal large intestine morphology … (more)
Abnormality of eye movement (present) , Abnormal cardiovascular system morphology (present) , Feeding difficulties (present) , Abnormal intestine morphology (present) , Abnormal large intestine morphology (present) , Developmental dysplasia of the hip (present) , Abnormal muscle physiology (present) , Cerebral palsy (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Seizure (present) , Decreased response to growth hormone stimulation test (present) , Abnormality of the amniotic fluid (present) , Premature birth (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2015-05-19
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Phenotypic abnormality (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic
Date variant was reported to submitter: 2020-11-05
Testing laboratory interpretation: Pathogenic
|
Comment:
Comment:
The Phe595Leu variant in BRAF has been reported in the literature in one individ ual with clinical features of Cardio-facio-cutaneous syndrome (CFC; Rodriguez-Vi ciana 2006). This same amino acid change caused by a different DNA change (c.178 5T>A) has also been reported to have occurred de novo in an individual with clin ical features of CFC syndrome (Schulz 2008). In addition, this variant was not i dentified in either parent of a proband (LMM unpublished data). Computational pr ediction tools and conservation analyses suggest that the Phe595Leu variant may impact the protein. In summary, this variant is likely pathogenic, though additi onal studies are required to fully establish its clinical significance.
Comment:
Variant summary: BRAF c.1785T>G (p.Phe595Leu) results in a non-conservative amino acid change located in the Protein Kinase Domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251240 control chromosomes (gnomAD). c.1785T>G has been reported in the literature in multiple individuals affected with Cardiofaciocutaneous Syndrome (examples: Rodrigues-Viciana_2006, Sarkozy_2009, Yoon_2007, Pierpont_2010, Abe_2012, Alfieri_2013, Lee_2021). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant has been reviewed and classified as pathogenic by the ClinGen RASopathy Expert Panel (Gelb et al., 2018); This variant is associated with the following publications: (PMID: 16439621, 18042262, 12068308, 32269299, 29752777, 33040082, 26582644, 30138938, 24957944, 15488754, 29493581, 15520807, 17603483, 23093928, 30977659, 32913992, 29084544, 19206169)
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt BRAF protein function. ClinVar contains an entry for this variant (Variation ID: 177672). This missense change has been observed in individual(s) with BRAF-related conditions (PMID: 16439621, 29084544, 33040082, 33318624). In at least one individual the variant was observed to be de novo. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 595 of the BRAF protein (p.Phe595Leu).
Comment:
Variant was identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 05-19-2015 by lab or GTR ID GeneDx. Variant interpreted as Pathogenic and reported on 11-05-2020 by lab or GTR ID Mayo Clinic. GenomeConnect - CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The c.1785T>G (p.Phe595Leu) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 19206169, 18042262; GTR ID's: 26957, 21766; ClinVar SCV000203922.4, SCV000207755.12). The variant has also been identified in at least 2 independent occurences in patients with clinical features of a RASopathy (PS4_Supporting; APHP-Robert Debré internal data; GTR ID 28338). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581, 16439621). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe595Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM2, PM1, PP2, PP3, PS4_Supporting.
Comment:
The Phe595Leu variant in BRAF has been reported in the literature in one individ ual with clinical features of Cardio-facio-cutaneous syndrome (CFC; Rodriguez-Vi ciana 2006). This same amino acid change caused by a different DNA change (c.178 5T>A) has also been reported to have occurred de novo in an individual with clin ical features of CFC syndrome (Schulz 2008). In addition, this variant was not i dentified in either parent of a proband (LMM unpublished data). Computational pr ediction tools and conservation analyses suggest that the Phe595Leu variant may impact the protein. In summary, this variant is likely pathogenic, though additi onal studies are required to fully establish its clinical significance.
Comment:
Variant summary: BRAF c.1785T>G (p.Phe595Leu) results in a non-conservative amino acid change located in the Protein Kinase Domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251240 control chromosomes (gnomAD). c.1785T>G has been reported in the literature in multiple individuals affected with Cardiofaciocutaneous Syndrome (examples: Rodrigues-Viciana_2006, Sarkozy_2009, Yoon_2007, Pierpont_2010, Abe_2012, Alfieri_2013, Lee_2021). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant has been reviewed and classified as pathogenic by the ClinGen RASopathy Expert Panel (Gelb et al., 2018); This variant is associated with the following publications: (PMID: 16439621, 18042262, 12068308, 32269299, 29752777, 33040082, 26582644, 30138938, 24957944, 15488754, 29493581, 15520807, 17603483, 23093928, 30977659, 32913992, 29084544, 19206169)
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt BRAF protein function. ClinVar contains an entry for this variant (Variation ID: 177672). This missense change has been observed in individual(s) with BRAF-related conditions (PMID: 16439621, 29084544, 33040082, 33318624). In at least one individual the variant was observed to be de novo. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 595 of the BRAF protein (p.Phe595Leu).
Comment:
Variant was identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 05-19-2015 by lab or GTR ID GeneDx. Variant interpreted as Pathogenic and reported on 11-05-2020 by lab or GTR ID Mayo Clinic. GenomeConnect - CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genotype-phenotype association by echocardiography offers incremental value in patients with Noonan Syndrome with Multiple Lentigines. | Kauffman H | Pediatric research | 2021 | PMID: 33318624 |
| Clinical and molecular spectra of BRAF-associated RASopathy. | Lee Y | Journal of human genetics | 2021 | PMID: 33040082 |
| Clinical Application of Targeted Deep Sequencing in Metastatic Colorectal Cancer Patients: Actionable Genomic Alteration in K-MASTER Project. | Lee Y | Cancer research and treatment | 2021 | PMID: 32810930 |
| Study of Ras/MAPK pathway gene variants in Chilean patients with Cryptorchidism. | Rodríguez F | Andrology | 2018 | PMID: 29752777 |
| ClinGen's RASopathy Expert Panel consensus methods for variant interpretation. | Gelb BD | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29493581 |
| Targeted/exome sequencing identified mutations in ten Chinese patients diagnosed with Noonan syndrome and related disorders. | Xu S | BMC medical genomics | 2017 | PMID: 29084544 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Behavioral profile in RASopathies. | Alfieri P | American journal of medical genetics. Part A | 2014 | PMID: 24458522 |
| A structural systems biology approach for quantifying the systemic consequences of missense mutations in proteins. | Cheng TM | PLoS computational biology | 2012 | PMID: 23093928 |
| Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a nationwide epidemiological survey. | Abe Y | American journal of medical genetics. Part A | 2012 | PMID: 22495831 |
| Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome. | Pierpont EI | American journal of medical genetics. Part A | 2010 | PMID: 20186801 |
| Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. | Sarkozy A | Human mutation | 2009 | PMID: 19206169 |
| Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. | Schulz AL | Clinical genetics | 2008 | PMID: 18042262 |
| Neurological complications of cardio-facio-cutaneous syndrome. | Yoon G | Developmental medicine and child neurology | 2007 | PMID: 18039235 |
| Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. | Rodriguez-Viciana P | Science (New York, N.Y.) | 2006 | PMID: 16439621 |
| Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. | Wan PT | Cell | 2004 | PMID: 15035987 |
| DNA ploidy in nonseminomatous germ cell testicular tumor. | Moul JW | Urology | 1994 | PMID: 8042262 |
| http://docm.genome.wustl.edu/variants/ENST00000288602:c.1785T>G | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/020e6a22-3189-484a-8ca8-77cd1a08adba | - | - | - | - |
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Text-mined citations for rs121913341 ...
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the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
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Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.