chr2-39056704-T-C

Variant names:

• chr2-39056704-T-C
• rs397517172
• NM_005633.4:c.508A>G
• SOS1 p.Lys170Glu

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 18 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PP3_ModeratePP5_Very_Strong

The NM_005633.4(SOS1):c.508A>G (p.Lys170Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. 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: 7.91). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000062238: functional data indicates that this variant leads to gain-of-function (Lee 2011)" and additional evidence is available in ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.K170Q: Uncertain_significance (ClinVar VariationId 2443406, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense, splice_region
• Scores: Splicing: ADA: 0.4589
• Clinical Significance: Pathogenic reviewed by expert panel P:23
• Conservation: PhyloP100: 7.91
• Publications: 19 publications found

Genes affected

SOS1 (HGNC:11187): (SOS Ras/Rac guanine nucleotide exchange factor 1) This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]

SOS1 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, PanelApp Australia
• fibromatosis, gingival, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary gingival fibromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cardiofaciocutaneous syndrome

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Specifications for SOS1 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 18 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000062238: functional data indicates that this variant leads to gain-of-function (Lee 2011); SCV000616383: "In vitro functional studies provide some evidence that the p.Lys170Glu variant may impact protein function (PS3; PMID 21784453, 23487764)."; SCV000209094: Published functional studies demonstrate enhanced activity of the Ras-MAPK pathway (PMID: 21784453, 23487764); SCV000553270: Experimental studies have shown that this missense change affects SOS1 function (PMID: 21784453).; SCV001363487: Two functional studies showed that this variant had a gain-of-function effect (Lee_2011, Smith_2013).; SCV001160005: Functional analyses of the variant protein shows increased activation of Ras and ERK, due to structural changes in the autoinhibitory HF domain (Lee 2011, Smith 2013).; SCV002073352: Functional studies depict a damaging effect (Smith MJ et al; Lee BH et al).; SCV006584951: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21784453, 23487764).; SCV002646037: Two in vitro functional studies have found this alteration results in significantly increased activation of the Ras pathway (Lee BH et al. J Pediatr. 2011;159(6):1029-35; Smith MJ et al. Proc Natl Acad Sci USA. 2013;110(12):4574-9).; SCV004737506: Functional studies demonstrate this variant results in increased RAS activation, p-ERK levels, and GDP-to-GTP exchange rate, consistent with a gain-of-function mechanism, resulting in hyperactivation of the RAS pathway (Lee et al. 2011. PubMed ID: 21784453; Smith et al. 2013. PubMed ID: 23487764).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 3 pathogenic, 0 benign (OR vs. background: 35.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (23/23 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005633.4. 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
	SOS1 NM_005633.4	MANE Select	c.508A>G p.Lys170Glu	missensesplice_region	Exon 4 of 23	Prot: NP_005624.2
	SOS1 NM_001382394.1		c.487A>G p.Lys163Glu	missensesplice_region	Exon 4 of 23	Prot: NP_001369323.1
	SOS1 NM_001382395.1		c.508A>G p.Lys170Glu	missensesplice_region	Exon 4 of 22	Prot: NP_001369324.1 UniProt:

SOS1 NM_005633.4

MANE Select

HGVSc / HGVSpc.508A>Gp.Lys170Glu

Exon rankExon 4 of 23

missensesplice_region

Prot: NP_005624.2

SOS1 NM_001382394.1

HGVSc / HGVSpc.487A>Gp.Lys163Glu

Exon rankExon 4 of 23

missensesplice_region

Prot: NP_001369323.1

SOS1 NM_001382395.1

HGVSc / HGVSpc.508A>Gp.Lys170Glu

Exon rankExon 4 of 22

missensesplice_region

Prot: NP_001369324.1UniProt: G5E9C8

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SOS1 ENST00000402219.8	TSL:1MANE Select	c.508A>G p.Lys170Glu	missensesplice_region	Exon 4 of 23	Prot: ENSP00000384675.2 UniProt:
	SOS1 ENST00000395038.6	TSL:5	c.508A>G p.Lys170Glu	missensesplice_region	Exon 4 of 22	Prot: ENSP00000378479.2 UniProt:
	SOS1 ENST00000913801.1		c.508A>G p.Lys170Glu	missensesplice_region	Exon 4 of 22	Prot: ENSP00000583860.1 UniProt:

SOS1 ENST00000402219.8

TSL:1MANE Select

HGVSc / HGVSpc.508A>Gp.Lys170Glu

Exon rankExon 4 of 23

missensesplice_region

Prot: ENSP00000384675.2UniProt: Q07889-1

SOS1 ENST00000395038.6

TSL:5

HGVSc / HGVSpc.508A>Gp.Lys170Glu

Exon rankExon 4 of 22

missensesplice_region

Prot: ENSP00000378479.2UniProt: G5E9C8

SOS1 ENST00000913801.1

HGVSc / HGVSpc.508A>Gp.Lys170Glu

Exon rankExon 4 of 22

missensesplice_region

Prot: ENSP00000583860.1UniProt: A0ACI8SNT2

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:27
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:187114	Cov:

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	48450	0.0000268	2	74550

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
7	-	-	Noonan syndrome 4 (7)
2	-	-	Noonan syndrome (2)
2	-	-	RASopathy (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Neonatal hypotonia (1)
1	-	-	not specified (1)
1	-	-	SOS1-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
GPN-Star LLR	N/A	-9.6
GPN-Star score	N/A	9.6
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.31	D
Mutation Taster	N/A	2/98	disease causing (ClinVar)
MutationAssessor	Benign	2.0	M
PhyloP100	Pathogenic	7.9
popEVE	Benign	-3.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.5	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.88
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.022	D
Varity_R	N/A	0.92
VESM-3B	Benign	-11

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.46
dbscSNV1_RF	Benign	0.51
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 4 of 4 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: rs397517172;

hg19: chr2-39283845;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar