Submissions for variant NM_004333.6(BRAF):c.1802A>C (p.Lys601Thr)

dbSNP: rs397507484

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003539772	SCV004280761	pathogenic	RASopathy	2023-08-04	criteria provided, single submitter	clinical testing	Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BRAF function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Lys601 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19206169). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 44818). This missense change has been observed in individuals with clinical features of BRAF-related conditions (PMID: 22495831, 28832562, 29453417). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 601 of the BRAF protein (p.Lys601Thr).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037939	SCV000061604	pathogenic	Noonan syndrome; Cardio-facio-cutaneous syndrome	2014-07-16	no assertion criteria provided	clinical testing	The Lys601Thr variant in BRAF has been reported in four individuals with clinica l features of Noonan syndrome and Cardio-facio-cutaneous (CFC) syndrome (Abe 201 2, LMM unpublished data). Parental testing showed that this variant occurred de novo in one of these individuals (LMM unpublished data). This variant was absent from large population studies. Different amino acid changes at this location ha ve been identified in affected individuals; the Lys601Gln was identified as a de novo variant in two individuals with clinical features of CFC syndrome (Sarkozy 2009) and the Lys601Ile variant was identified in one individual with clinical features of CFC syndrome (Lepri 2014), suggesting that changes at this position are not tolerated. Additionally, computational prediction tools and evolutionary conservation analysis suggest that the Lys601Thr variant may impact the protein . In summary, the Lys601Thr variant meets our criteria to be classified as patho genic (http://pcpgm.partners.org/LMM).
Database of Curated Mutations (DoCM)	RCV000444564	SCV000505838	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425098	SCV000505839	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434946	SCV000505840	likely pathogenic	Thyroid tumor	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417689	SCV000505841	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431024	SCV000505842	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438200	SCV000505843	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420107	SCV000505844	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
GenomeConnect - CFC International	RCV000999627	SCV001156337	not provided	Cardiofaciocutaneous syndrome 1		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 02-06-2018 by Lab or GTR ID High Medic Group Associated Laboratories. 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.