chr2-47475130-C-T

Variant names:

• chr2-47475130-C-T
• rs28929483
• NM_000251.3:c.1865C>T
• MSH2 p.Pro622Leu

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 (ACGS-UK Somatic Oncogenicity v2025). O1_ModerateO3_ModerateO5_SupportingO6_Supporting

The NM_000251.3(MSH2):c.1865C>T (p.Pro622Leu) variant causes a missense change involving the alteration of a 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 allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,872 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.20). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV006586619: Functional studies indicate this variant impacts protein function [PMID:22102614, 21309037, 26951660, 33357406]." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.P622T: Pathogenic/Likely_pathogenic (ClinVar VariationId 90805, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P622A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 186899); p.P622= (synonymous): Benign/Likely_benign (ClinVar VariationId 232372, 2 stars); p.P622= (synonymous): Likely_benign (ClinVar VariationId 1078844, 1 star) The variant has been observed in cBioPortal in 2 samples across 2 studies and 2 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.21
• Publications: 21 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: Likely_pathogenic. The variant received 6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (2.0 pts): ClinVar germline P/LP in TSG (★★★)
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000001, AC = 1 — absent/extremely rare (O3 moderate [+2])
	O5Same location/impact as known oncogenic		Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect

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.1865C>T p.Pro622Leu	missense	Exon 12 of 16	Prot: NP_000242.1 UniProt:
	MSH2 NM_001406674.1		c.1865C>T p.Pro622Leu	missense	Exon 12 of 18	Prot: NP_001393603.1
	MSH2 NM_001406631.1		c.1865C>T p.Pro622Leu	missense	Exon 12 of 18	Prot: NP_001393560.1

MSH2 NM_000251.3

MANE Select

HGVSc / HGVSpc.1865C>Tp.Pro622Leu

Exon rankExon 12 of 16

missense

Prot: NP_000242.1UniProt: P43246-1

MSH2 NM_001406674.1

HGVSc / HGVSpc.1865C>Tp.Pro622Leu

Exon rankExon 12 of 18

missense

Prot: NP_001393603.1

MSH2 NM_001406631.1

HGVSc / HGVSpc.1865C>Tp.Pro622Leu

Exon rankExon 12 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.1865C>T p.Pro622Leu	missense	Exon 12 of 16	Prot: ENSP00000233146.2 UniProt:
	MSH2 ENST00000406134.5	TSL:1	c.1865C>T p.Pro622Leu	missense	Exon 12 of 16	Prot: ENSP00000384199.1 UniProt:
	MSH2 ENST00000918107.1		c.1916C>T p.Pro639Leu	missense	Exon 13 of 17	Prot: ENSP00000588166.1 UniProt:

MSH2 ENST00000233146.7

TSL:1MANE Select

HGVSc / HGVSpc.1865C>Tp.Pro622Leu

Exon rankExon 12 of 16

missense

Prot: ENSP00000233146.2UniProt: P43246-1

MSH2 ENST00000406134.5

TSL:1

HGVSc / HGVSpc.1865C>Tp.Pro622Leu

Exon rankExon 12 of 16

missense

Prot: ENSP00000384199.1UniProt: E9PHA6

MSH2 ENST00000918107.1

HGVSc / HGVSpc.1916C>Tp.Pro639Leu

Exon rankExon 13 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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461872	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:204212	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Lynch syndrome (2)
2	-	-	Lynch syndrome 1 (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	29
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-7.3
GPN-Star score	N/A	7.3
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	5/95	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.9	H
PhyloP100	Uncertain	7.2
popEVE	Benign	-4.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-9.6	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.94
VESM-3B	Benign	-13

Showing 28 of 28 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.

1 abnormal

1 assay found for this variant.

Clinical calibration: 1 functionally abnormal (PS3), 0 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: 2.29 · p.Pro622Leu (assay numbering)

Classified as

PS3 strongFunctionally abnormalScott calibration: Loss of function

+4 more calibrations

PS3 strongFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Loss of function

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: Loss of function

PS3 strongFunctionally abnormalRUO ExCALIBR calibration (ClinVar 2018): PS3 Strong (5)

PS3 moderate plusFunctionally abnormalRUO ExCALIBR calibration: PS3 Moderate+ (3)

Other links and lift over

dbSNP: rs28929483;

hg19: chr2-47702269;

COSMIC: COSV99253264;

COSMIC: COSV99253264;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar