NM_000251.3:c.2038C>T

Variant names:

• chr2-47476399-C-T
• rs63749932
• NM_000251.3:c.2038C>T
• MSH2 p.Arg680*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 22 classification points (ACMG Germline Pathogenicity v2019). PVS1PS3PM2PP5_Very_Strong

The NM_000251.3(MSH2):c.2038C>T (p.Arg680*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.00000137 (AC=2) in the gnomAD database across 1,461,874 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (BayesDel (noAF)) 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 Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV004699464: PS3:Supporting". 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: 0.0000014 (0 hom.)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:24 U:1
• Conservation: PhyloP100: 5.72
• Publications: 46 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 ACMG Germline Pathogenicity v2019

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: Pathogenic. The variant received 22 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 13 of 16) at amino acid 680 of 934, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV004699464: PS3:Supporting
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00268) — PM2 moderate.
	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 (24/25 total P/LP).

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.2038C>T p.Arg680*	stop_gained	Exon 13 of 16	Prot: NP_000242.1 UniProt:
	MSH2 NM_001406674.1		c.2038C>T p.Arg680*	stop_gained	Exon 13 of 18	Prot: NP_001393603.1
	MSH2 NM_001406631.1		c.2038C>T p.Arg680*	stop_gained	Exon 13 of 18	Prot: NP_001393560.1

MSH2 NM_000251.3

MANE Select

HGVSc / HGVSpc.2038C>Tp.Arg680*

Exon rankExon 13 of 16

stop_gained

Prot: NP_000242.1UniProt: P43246-1

MSH2 NM_001406674.1

HGVSc / HGVSpc.2038C>Tp.Arg680*

Exon rankExon 13 of 18

stop_gained

Prot: NP_001393603.1

MSH2 NM_001406631.1

HGVSc / HGVSpc.2038C>Tp.Arg680*

Exon rankExon 13 of 18

stop_gained

Prot: NP_001393560.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MSH2 ENST00000233146.7	TSL:1MANE Select	c.2038C>T p.Arg680*	stop_gained	Exon 13 of 16	Prot: ENSP00000233146.2 UniProt:
	MSH2 ENST00000406134.5	TSL:1	c.2038C>T p.Arg680*	stop_gained	Exon 13 of 16	Prot: ENSP00000384199.1 UniProt:
	MSH2 ENST00000918107.1		c.2089C>T p.Arg697*	stop_gained	Exon 14 of 17	Prot: ENSP00000588166.1 UniProt:

MSH2 ENST00000233146.7

TSL:1MANE Select

HGVSc / HGVSpc.2038C>Tp.Arg680*

Exon rankExon 13 of 16

stop_gained

Prot: ENSP00000233146.2UniProt: P43246-1

MSH2 ENST00000406134.5

TSL:1

HGVSc / HGVSpc.2038C>Tp.Arg680*

Exon rankExon 13 of 16

stop_gained

Prot: ENSP00000384199.1UniProt: E9PHA6

MSH2 ENST00000918107.1

HGVSc / HGVSpc.2089C>Tp.Arg697*

Exon rankExon 14 of 17

stop_gained

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251446	Cov:
GnomAD4 exome	AF: 0.00000137	AC:2	Hom:0	AN:1461874	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:217698	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
Epi25(Epilepsy)	0.0000238	1	41958	0.00	0	66888
SCHEMA(Schizophrenia)	0.00	0	67520	0.00000754	1	132634

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	1	-	not provided (9)
7	-	-	Lynch syndrome 1 (7)
3	-	-	Lynch syndrome (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Lynch syndrome 4 (1)
1	-	-	Lynch-like syndrome (1)
1	-	-	Malignant tumor of ascending colon (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	40
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	54
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Uncertain	5.7
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7

Showing 14 of 14 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.15
Pangolin loss	Benign	0.15	Position offset: -32
SpliceAI score (max)	Benign	0.030	Details are displayed if max score is > 0.2

Showing 3 of 3 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: rs63749932;

hg19: chr2-47703538;

COSMIC: COSV51875657;

COSMIC: COSV51875657;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar