2-47403329-C-A

Variant names:

• chr2-47403329-C-A
• NM_000251.3:c.138C>A
• MSH2 p.His46Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_SupportingB2_Supporting

The NM_000251.3(MSH2):c.138C>A (p.His46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene MSH2 is a tumor suppressor gene (CancerMine: 4 TSG, 3 oncogene, 1 driver citations). The gene MSH2 is a known oncogene (CancerMine: 4 TSG, 3 oncogene, 1 driver citations). The gene MSH2 is a cancer driver gene (CancerMine: 4 TSG, 3 oncogene, 1 driver citations). 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. Variant has been reported in ClinVar as Benign/Likely Benign (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.H46D: Uncertain_significance (ClinVar VariationId 1058599, 1 star); p.H46= (synonymous): Benign/Likely_benign (ClinVar VariationId 491770, 2 stars); p.H46P: Uncertain_significance (ClinVar VariationId 525765, 2 stars); p.H46Q: Likely_benign (ClinVar VariationId 90654, 3 stars); p.H46Y: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 483663) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.26
• Publications: 0 publications found

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

MSH2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Muir-Torre syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for MSH2 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 2 points.

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])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	B2Does not fit gene mode of action		Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context); Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000251.3. 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
	MSH2 NM_000251.3	MANE Select	c.138C>A p.His46Gln	missense	Exon 1 of 16	Prot: NP_000242.1 UniProt:
	MSH2 NM_001406674.1		c.138C>A p.His46Gln	missense	Exon 1 of 18	Prot: NP_001393603.1
	MSH2 NM_001406631.1		c.138C>A p.His46Gln	missense	Exon 1 of 18	Prot: NP_001393560.1

MSH2 NM_000251.3

MANE Select

HGVSc / HGVSpc.138C>Ap.His46Gln

Exon rankExon 1 of 16

missense

Prot: NP_000242.1UniProt: P43246-1

MSH2 NM_001406674.1

HGVSc / HGVSpc.138C>Ap.His46Gln

Exon rankExon 1 of 18

missense

Prot: NP_001393603.1

MSH2 NM_001406631.1

HGVSc / HGVSpc.138C>Ap.His46Gln

Exon rankExon 1 of 18

missense

Prot: NP_001393560.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MSH2 ENST00000233146.7	TSL:1MANE Select	c.138C>A p.His46Gln	missense	Exon 1 of 16	Prot: ENSP00000233146.2 UniProt:
	MSH2 ENST00000406134.5	TSL:1	c.138C>A p.His46Gln	missense	Exon 1 of 16	Prot: ENSP00000384199.1 UniProt:
	MSH2 ENST00000918107.1		c.138C>A p.His46Gln	missense	Exon 1 of 17	Prot: ENSP00000588166.1 UniProt:

MSH2 ENST00000233146.7

TSL:1MANE Select

HGVSc / HGVSpc.138C>Ap.His46Gln

Exon rankExon 1 of 16

missense

Prot: ENSP00000233146.2UniProt: P43246-1

MSH2 ENST00000406134.5

TSL:1

HGVSc / HGVSpc.138C>Ap.His46Gln

Exon rankExon 1 of 16

missense

Prot: ENSP00000384199.1UniProt: E9PHA6

MSH2 ENST00000918107.1

HGVSc / HGVSpc.138C>Ap.His46Gln

Exon rankExon 1 of 17

missense

Prot: ENSP00000588166.1UniProt: A0ACI8SWY1

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Lynch syndrome 1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
FuncVEP CTI	Pathogenic	0.95
GPN-Star LLR	N/A	-8.7
GPN-Star score	N/A	8.7
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.89	D
Mutation Taster	N/A	93/7	polymorphism
MutationAssessor	Pathogenic	3.6	H
PhyloP100	Benign	2.3
popEVE	Benign	-3.6
PrimateAI	Uncertain	0.78	T
PromoterAI	N/A	0.043	Neutral
PROVEAN	Pathogenic	-6.7	D
RBP_binding_hub_radar	N/A	0.97
RBP_regulation_power_radar	N/A	2.8
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Varity_R	N/A	0.98
VESM-3B	Benign	-9.6

Showing 31 of 31 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	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.

1 normal

1 assay found for this variant.

Clinical calibration: 0 functionally abnormal (PS3), 1 functionally normal (BS3).

Protein level

MSH2 LOF scores (HAP1)

MSH2 deep mutational scan

• Gene: MSH2
• Assay type: Cell fitness
• Mechanism: DNA and Mismatch repair
• Model system: Immortalized human cells (Homo sapiens)
• Score: -3.65 · p.His46Gln (assay numbering)

Classified as

BS3 strongFunctionally normalScott calibration: Normal

+4 more calibrations

BS3 strongFunctionally normalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: WT-like

BS3 moderateFunctionally normalIGVF Coding Variant Focus Group -- Controls: All Variants: WT-like

BS3 moderateFunctionally normalRUO ExCALIBR calibration: BS3 Moderate (-2)

BS3 supportingFunctionally normalRUO ExCALIBR calibration (ClinVar 2018): BS3 Supporting (-1)

Other links and lift over

hg19: chr2-47630468;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar