2-39056702-CTT-TTG

Variant names:

• chr2-39056702-CTT-TTG
• NM_005633.4:c.508_510delAAGinsCAA
• SOS1 p.Lys170Gln

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5

The NM_005633.4(SOS1):c.508_510delAAGinsCAA (p.Lys170Gln) variant causes a missense, splice region change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.91). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.K170E: Pathogenic (ClinVar VariationId 40651, 3 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.K170Q: Uncertain_significance (ClinVar VariationId 2443406, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 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: Likely_pathogenic. The variant received 6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.K170E: Pathogenic (ClinVar VariationId 40651, 3 stars); Other variants at the same amino acid residue (not pathogenic): p.K170Q: Uncertain_significance (ClinVar VariationId 2443406, 1 star)

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.508_510delAAGinsCAA p.Lys170Gln	missensesplice_region	N/A	Prot: NP_005624.2
	SOS1 NM_001382394.1		c.487_489delAAGinsCAA p.Lys163Gln	missensesplice_region	N/A	Prot: NP_001369323.1
	SOS1 NM_001382395.1		c.508_510delAAGinsCAA p.Lys170Gln	missensesplice_region	N/A	Prot: NP_001369324.1 UniProt:

SOS1 NM_005633.4

MANE Select

HGVSc / HGVSpc.508_510delAAGinsCAAp.Lys170Gln

Exon rankN/A

missensesplice_region

Prot: NP_005624.2

SOS1 NM_001382394.1

HGVSc / HGVSpc.487_489delAAGinsCAAp.Lys163Gln

Exon rankN/A

missensesplice_region

Prot: NP_001369323.1

SOS1 NM_001382395.1

HGVSc / HGVSpc.508_510delAAGinsCAAp.Lys170Gln

Exon rankN/A

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.508_510delAAGinsCAA p.Lys170Gln	missensesplice_region	N/A	Prot: ENSP00000384675.2 UniProt:
	SOS1 ENST00000395038.6	TSL:5	c.508_510delAAGinsCAA p.Lys170Gln	missensesplice_region	N/A	Prot: ENSP00000378479.2 UniProt:
	SOS1 ENST00000913801.1		c.508_510delAAGinsCAA p.Lys170Gln	missensesplice_region	N/A	Prot: ENSP00000583860.1 UniProt:

SOS1 ENST00000402219.8

TSL:1MANE Select

HGVSc / HGVSpc.508_510delAAGinsCAAp.Lys170Gln

Exon rankN/A

missensesplice_region

Prot: ENSP00000384675.2UniProt: Q07889-1

SOS1 ENST00000395038.6

TSL:5

HGVSc / HGVSpc.508_510delAAGinsCAAp.Lys170Gln

Exon rankN/A

missensesplice_region

Prot: ENSP00000378479.2UniProt: G5E9C8

SOS1 ENST00000913801.1

HGVSc / HGVSpc.508_510delAAGinsCAAp.Lys170Gln

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	7.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr2-39283843;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar