rs267607048

Variant names:

• chr10-110964362-A-G
• rs267607048
• NM_007373.4:c.4A>G
• SHOC2 p.Ser2Gly

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_StrongO3_Supporting

The NM_007373.4(SHOC2):c.4A>G (p.Ser2Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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). The variant allele was found at a cumulative frequency of 0.00000342 (AC=5) in the gnomAD database across 1,460,838 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.49). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000605107: Functional characterization of the p.Ser2Gly protein indicates enhanced myristoylation, and aberrant targeting of the SHOC2 to the cell membrane in the absence of growth factor signaling (Cordeddu 2009). PMID:19684605" and additional evidence is available in 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) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). The variant has been observed in cBioPortal in 3 samples across 2 studies and 3 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.). 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SHOC2 NM_007373.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:50 O:1
• Conservation: PhyloP100: 8.49
• Publications: 97 publications found

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

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 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		CGI exact DNA-change oncogenic — Strong (O1); O1 contributing sources (4.0 pts): CGI (Cancer Genome Interpreter)
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000015 — very rare (O3 supporting [+1])

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SHOC2 NM_007373.4	MANE Select	c.4A>G p.Ser2Gly	missense	Exon 2 of 9	Prot: NP_031399.2
	SHOC2 NM_001324336.2		c.4A>G p.Ser2Gly	missense	Exon 2 of 9	Prot: NP_001311265.1 UniProt:
	SHOC2 NM_001324337.2		c.4A>G p.Ser2Gly	missense	Exon 3 of 10	Prot: NP_001311266.1 UniProt:

SHOC2 NM_007373.4

MANE Select

HGVSc / HGVSpc.4A>Gp.Ser2Gly

Exon rankExon 2 of 9

missense

Prot: NP_031399.2

SHOC2 NM_001324336.2

HGVSc / HGVSpc.4A>Gp.Ser2Gly

Exon rankExon 2 of 9

missense

Prot: NP_001311265.1UniProt: Q9UQ13-1

SHOC2 NM_001324337.2

HGVSc / HGVSpc.4A>Gp.Ser2Gly

Exon rankExon 3 of 10

missense

Prot: NP_001311266.1UniProt: Q9UQ13-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SHOC2 ENST00000369452.9	TSL:1MANE Select	c.4A>G p.Ser2Gly	missense	Exon 2 of 9	Prot: ENSP00000358464.5 UniProt:
	SHOC2 ENST00000685059.1		c.4A>G p.Ser2Gly	missense	Exon 3 of 10	Prot: ENSP00000510210.1 UniProt:
	SHOC2 ENST00000688928.1		c.4A>G p.Ser2Gly	missense	Exon 2 of 9	Prot: ENSP00000509273.1 UniProt:

SHOC2 ENST00000369452.9

TSL:1MANE Select

HGVSc / HGVSpc.4A>Gp.Ser2Gly

Exon rankExon 2 of 9

missense

Prot: ENSP00000358464.5UniProt: Q9UQ13-1

SHOC2 ENST00000685059.1

HGVSc / HGVSpc.4A>Gp.Ser2Gly

Exon rankExon 3 of 10

missense

Prot: ENSP00000510210.1UniProt: Q9UQ13-1

SHOC2 ENST00000688928.1

HGVSc / HGVSpc.4A>Gp.Ser2Gly

Exon rankExon 2 of 9

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152166	Cov:32
GnomAD4 exome	AF: 0.00000342	AC:5	Hom:0	AN:1460838	Cov:31
GnomAD4 genome Warning	AF: 0.00000657	AC:1	Hom:0	AN:152166	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00000979	AC:2	Hom:0	AN:204292	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
27	-	-	Noonan syndrome-like disorder with loose anagen hair 1 (28)
11	-	-	not provided (11)
3	-	-	RASopathy (3)
2	-	-	Noonan syndrome (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Houge-Janssens syndrome 2 (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	Noonan syndrome-like disorder with loose anagen hair (1)
1	-	-	Pectus excavatum;C4478716:Noonan syndrome-like disorder with loose anagen hair 1 (1)
1	-	-	Polycystic kidney disease 4 (1)
1	-	-	SHOC2-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
GPN-Star LLR	N/A	-7.4
GPN-Star score	N/A	7.4
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.87	T
Mutation Taster	N/A	13/87	disease causing (ClinVar)
MutationAssessor	Benign	1.9	M
PhyloP100	Pathogenic	8.5
popEVE	Benign	-3.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.60	T
Varity_R	N/A	0.44
VESM-3B	Benign	-4.3

Showing 27 of 27 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: rs267607048;

hg19: chr10-112724120;

COSMIC: COSV54624833;

COSMIC: COSV54624833;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar