rs267607048

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PS3PM2_SupportingPP5_Very_Strong

The NM_007373.4(SHOC2):c.4A>G (p.Ser2Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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). 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: 87 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 ACMG Germline Pathogenicity v2019

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: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); 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; SCV000616382: "In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605)."; SCV002012001: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19684605).; SCV002767174: Functional studies have demonstrated this variant causes impaired nuclear translocation and MAPK activation (PMID: 19684605); Missense variants in this gene result in enhanced MAPK activation (OMIM, PMID: 19684605).; SCV004171888: Functional studies indicate that this variant has a damaging effect on the gene or the gene product (Cordeddu V, et. al., 2009).; SCV005685488: "In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function." PMID:19684605; SCV000253914: Experimental studies have shown that this missense change affects SHOC2 function (PMID: 19684605, 22606262).; SCV000699328: From functional studies this variant was found to introduce an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2-S2G in vitro enhanced MAPK activation in a cell type specific fashion. Induction of SHOC2-S2G in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype associated with aberrant signaling (Cordeddu_2009). In other functional study, the SHOC2-S2G mutant did not rescue ERK1/2 activation in Shoc2-depleted cells and the mutant was not located in late endosomes, however it was present on the plasma membrane and early endosomes (Galperin_2012).; SCV000062456: "In vitro functional studies provide some evidence that the p.Ser2Gly variant impacts protein function (Cordeddu 2009)."; SCV002817221: Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 19684605, 22606262).; SCV005350870: Functional studies found that this variant results in aberrant targeting of SHOC2 protein to the plasma membrane, impaired translocation to the nucleus upon growth factor stimulation, and enhanced MAPK activation in a cell type specific manner (Cordeddu et al. 2009. PubMed ID: 19684605).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000147 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
	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 (50/50 total P/LP).

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	NP_031399.2
	SHOC2	NM_001324336.2		c.4A>G	p.Ser2Gly	missense	Exon 2 of 9	NP_001311265.1	Q9UQ13-1
	SHOC2	NM_001324337.2		c.4A>G	p.Ser2Gly	missense	Exon 3 of 10	NP_001311266.1	Q9UQ13-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOC2	ENST00000369452.9	TSL:1 MANE Select	c.4A>G	p.Ser2Gly	missense	Exon 2 of 9	ENSP00000358464.5	Q9UQ13-1
	SHOC2	ENST00000685059.1		c.4A>G	p.Ser2Gly	missense	Exon 3 of 10	ENSP00000510210.1	Q9UQ13-1
	SHOC2	ENST00000688928.1		c.4A>G	p.Ser2Gly	missense	Exon 2 of 9	ENSP00000509273.1	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.

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