Genetic Variant SHOC2:p.Ser2Gly (chr10-110964362-AGT-GGG) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is The variant received 4 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO5_Moderate

The NM_007373.4(SHOC2):c.4_6delAGTinsGGG (p.Ser2Gly) variant causes a missense change. The gene SHOC2 is a known oncogene (CancerMine: 2 oncogene, 1 driver citations). The gene SHOC2 is a cancer driver gene (CancerMine: 2 oncogene, 1 driver citations). 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: 9.11). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S2T: Uncertain_significance (ClinVar VariationId 2265459, 1 star) The same amino acid change has been reported as oncogenic or likely oncogenic in a clinical somatic variant database. This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: not found (cov: 32)

Consequence

SHOC2
NM_007373.4 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.11

Publications

0 publications found

Variant links:

Genes affected

SHOC2 (HGNC:15454): (SHOC2 leucine rich repeat scaffold protein) This gene encodes a protein that consists almost entirely of leucine-rich repeats, a domain implicated in protein-protein interactions. The protein may function as a scaffold linking RAS to downstream signal transducers in the RAS/ERK MAP kinase signaling cascade. Mutations in this gene have been associated with Noonan-like syndrome with loose anagen hair. [provided by RefSeq, May 2010]

SHOC2 Gene-Disease associations (from GenCC):

Noonan syndrome-like disorder with loose anagen hair
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Noonan syndrome-like disorder with loose anagen hair 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SHOC2 links:

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new If you want to explore the variant's impact on the transcript NM_007373.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for SHOC2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 4 points.

Show applied only (2)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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])
	O5Same location/impact as known oncogenic		Same AA change as established oncogenic variant (or germline P/LP in TSG) — Moderate (O5); ClinVar same-AA oncogenic/T1: false \| ClinVar same-AA SCI tier: — \| CGI same-AA oncogenic: true \| TSG: false \| ClinVar same-AA germline P/LP: true \| CIViC LOF: false \| ClinVar diff-AA oncogenic: false \| ClinVar diff-AA germline P/LP: false

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_007373.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
SHOC2 NM_007373.4	MANE Select	c.4_6delAGTinsGGG p.Ser2Gly	missense	N/A	Prot: NP_031399.2
SHOC2 NM_001324336.2		c.4_6delAGTinsGGG p.Ser2Gly	missense	N/A	Prot: NP_001311265.1 UniProt: Q9UQ13-1
SHOC2 NM_001324337.2		c.4_6delAGTinsGGG p.Ser2Gly	missense	N/A	Prot: NP_001311266.1 UniProt: Q9UQ13-1

SHOC2 NM_007373.4

MANE Select

HGVSc / HGVSpc.4_6delAGTinsGGGp.Ser2Gly

Exon rankN/A

missense

Prot: NP_031399.2

SHOC2 NM_001324336.2

HGVSc / HGVSpc.4_6delAGTinsGGGp.Ser2Gly

Exon rankN/A

missense

Prot: NP_001311265.1UniProt: Q9UQ13-1

SHOC2 NM_001324337.2

HGVSc / HGVSpc.4_6delAGTinsGGGp.Ser2Gly

Exon rankN/A

missense

Prot: NP_001311266.1UniProt: Q9UQ13-1

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
SHOC2 ENST00000369452.9	TSL:1MANE Select	c.4_6delAGTinsGGG p.Ser2Gly	missense	N/A	Prot: ENSP00000358464.5 UniProt: Q9UQ13-1
SHOC2 ENST00000685059.1		c.4_6delAGTinsGGG p.Ser2Gly	missense	N/A	Prot: ENSP00000510210.1 UniProt: Q9UQ13-1
SHOC2 ENST00000688928.1		c.4_6delAGTinsGGG p.Ser2Gly	missense	N/A	Prot: ENSP00000509273.1 UniProt: Q9UQ13-1

SHOC2 ENST00000369452.9

TSL:1MANE Select

HGVSc / HGVSpc.4_6delAGTinsGGGp.Ser2Gly

Exon rankN/A

missense

Prot: ENSP00000358464.5UniProt: Q9UQ13-1

SHOC2 ENST00000685059.1

HGVSc / HGVSpc.4_6delAGTinsGGGp.Ser2Gly

Exon rankN/A

missense

Prot: ENSP00000510210.1UniProt: Q9UQ13-1

SHOC2 ENST00000688928.1

HGVSc / HGVSpc.4_6delAGTinsGGGp.Ser2Gly

Exon rankN/A

missense

Prot: ENSP00000509273.1UniProt: Q9UQ13-1

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

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.1

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence