3-12604200-G-A

Variant names:

• chr3-12604200-G-A
• rs80338796
• NM_002880.4:c.770C>T
• RAF1 p.Ser257Leu

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 17 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_Very_StrongO3_ModerateO4_ModerateO6_SupportingO7_Strong

The NM_002880.4(RAF1):c.770C>T (p.Ser257Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The gene RAF1 is a known oncogene (CancerMine: 1 TSG, 57 oncogene, 3 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 10.00). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV002521319: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:17603482, 20052757)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.S257T: Likely_pathogenic (ClinVar VariationId 618340, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S257= (synonymous): Likely_benign (ClinVar VariationId 1112676, 1 star); p.S257W: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 376514) This exact variant is established as oncogenic in: ClinVar, CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 25 samples carry this exact amino acid change out of 50 samples with a variant at this residue. The variant has been observed in cBioPortal in 240 samples across 66 studies and 51 cancer types; somatic enrichment level: MODERATE (Observed in many cases across multiple studies/cancer contexts.). This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Noonan syndrome 5 (ns5); it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAF1 NM_002880.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:45 O:3
• Conservation: PhyloP100: 10.0
• Publications: 1 publications found

Genes affected

RAF1 (HGNC:9829): (Raf-1 proto-oncogene, serine/threonine kinase) This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]

RAF1 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
• dilated cardiomyopathy 1NN

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• LEOPARD syndrome 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for RAF1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		ClinVar oncogenic AND CGI oncogenic — two independent sources, Very Strong (O1); CGI exact DNA-change oncogenic — Strong (O1); ClinVar SCI Tier II Potential (capped at Moderate regardless of stars) — Moderate (O1); O1 contributing sources (8.0 pts): ClinVar SCI Tier II Potential (★★★), CGI (Cancer Genome Interpreter)
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 2.0) — Moderate (O4); cBioPortal: samples=240 | studies=66 | cancer types=51 | level=MODERATE | points=2.0 | reason: Observed in many cases across multiple studies/cancer contexts.
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Strong hotspot (cancerhotspots.org): >50 total samples, ≥10 same AA change; Note: exclude MSK/TCGA-derived samples from cancerhotspots count to avoid double-counting with O4; cancerhotspots.org: total samples at AA position = 50, same AA change = 25; Exclude MSK/TCGA-derived samples from count to avoid double-counting with O4; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 31 pathogenic, 0 benign (OR vs. background: 315.0); Variant does not impact splicing — splice-hotspot path not applicable

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002880.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RAF1 NM_002880.4	MANE Select	c.770C>T p.Ser257Leu	missense	Exon 7 of 17	Prot: NP_002871.1 UniProt:
	RAF1 NM_001354689.3		c.770C>T p.Ser257Leu	missense	Exon 7 of 18	Prot: NP_001341618.1 UniProt:
	RAF1 NM_001354690.3		c.770C>T p.Ser257Leu	missense	Exon 7 of 17	Prot: NP_001341619.1 UniProt:

RAF1 NM_002880.4

MANE Select

HGVSc / HGVSpc.770C>Tp.Ser257Leu

Exon rankExon 7 of 17

missense

Prot: NP_002871.1UniProt: L7RRS6P04049-1

RAF1 NM_001354689.3

HGVSc / HGVSpc.770C>Tp.Ser257Leu

Exon rankExon 7 of 18

missense

Prot: NP_001341618.1UniProt: P04049-2A0A0S2Z559

RAF1 NM_001354690.3

HGVSc / HGVSpc.770C>Tp.Ser257Leu

Exon rankExon 7 of 17

missense

Prot: NP_001341619.1UniProt: L7RRS6P04049-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RAF1 ENST00000251849.9	TSL:1MANE Select	c.770C>T p.Ser257Leu	missense	Exon 7 of 17	Prot: ENSP00000251849.4 UniProt:
	RAF1 ENST00000442415.7	TSL:5	c.770C>T p.Ser257Leu	missense	Exon 7 of 18	Prot: ENSP00000401888.2 UniProt:
	RAF1 ENST00000900382.1		c.770C>T p.Ser257Leu	missense	Exon 7 of 18	Prot: ENSP00000570441.1 UniProt:

RAF1 ENST00000251849.9

TSL:1MANE Select

HGVSc / HGVSpc.770C>Tp.Ser257Leu

Exon rankExon 7 of 17

missense

Prot: ENSP00000251849.4UniProt: P04049-1

RAF1 ENST00000442415.7

TSL:5

HGVSc / HGVSpc.770C>Tp.Ser257Leu

Exon rankExon 7 of 18

missense

Prot: ENSP00000401888.2UniProt: P04049-2

RAF1 ENST00000900382.1

HGVSc / HGVSpc.770C>Tp.Ser257Leu

Exon rankExon 7 of 18

missense

Prot: ENSP00000570441.1UniProt: P04049-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:207520	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
13	-	-	Noonan syndrome 5 (14)
12	-	-	not provided (12)
4	-	-	Noonan syndrome 1 (4)
3	-	-	LEOPARD syndrome 2;C1969057:Noonan syndrome 5;C4014656:Dilated cardiomyopathy 1NN (3)
3	-	-	Noonan syndrome (3)
3	-	-	RASopathy (3)
2	-	-	LEOPARD syndrome 2 (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines (1)
1	-	-	RAF1-related disorder (1)
1	-	-	See cases (1)
-	-	-	Embryonal rhabdomyosarcoma (1)
-	-	-	Noonan syndrome with multiple lentigines (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-9.2
GPN-Star score	N/A	9.2
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.10	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.0	M
PhyloP100	Pathogenic	10
popEVE	Benign	-4.2
PrimateAI	Pathogenic	0.82	D
PromoterAI	N/A	-0.044	Neutral
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.015	D
Varity_R	N/A	0.89
VESM-3B	Benign	-13

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs80338796;

hg19: chr3-12645699;

COSMIC: COSV52574378;

COSMIC: COSV52574378;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar