2-47475042-C-T

Variant names:

• chr2-47475042-C-T
• rs63750200
• NM_000251.3:c.1777C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.1777C>T​(p.Gln593*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q593Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.21
• Publications: 10 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: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47475042-C-T is Pathogenic according to our data. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475042-C-T is described in CliVar as Pathogenic. Clinvar id is 90783.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1777C>T	p.Gln593*	stop_gained	Exon 12 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1777C>T	p.Gln593*	stop_gained	Exon 12 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Jan 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Lynch syndrome Pathogenic:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Coding sequence variation introducing premature termination codon -

Lynch-like syndrome Pathogenic:1

Jul 01, 2019

Constitutional Genetics Lab, Leon Berard Cancer Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 30, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90783). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15235038, 27601186). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln593*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 10, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q593* pathogenic mutation (also known as c.1777C>T), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1777. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This mutation has been reported in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, including patients meeting Amsterdam criteria and/or whose tumors demonstrated loss of MSH2 by immunohistochemistry (IHC) (Naseem H et al. Clin Genet, 2006 Nov;70:388-95; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Sunga AY et al. Cancer Genet, 2017 04;212-213:1-7; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739; Tian W et al. Int J Cancer, 2019 09;145:1290-1298; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.2
Vest4		0.98
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs63750200; hg19: chr2-47702181;