2-47476492-C-T

Variant names:

• chr2-47476492-C-T
• rs63750636
• NM_000251.3:c.2131C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.2131C>T​(p.Arg711*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000124 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:25 U:1
• Conservation: PhyloP100: 3.72

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 2-47476492-C-T is Pathogenic according to our data. Variant chr2-47476492-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 90903.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476492-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2131C>T	p.Arg711*	stop_gained	Exon 13 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2131C>T	p.Arg711*	stop_gained	Exon 13 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74266

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000224 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:8

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 23, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Arg711X variant has been previously reported in the literature in numerous publications in families with Lynch syndrome (selected publications: Levati 1998, Mangold 2005, Parc 2003, Tanyi 2008). This variant leads to a premature stop codon at position 711, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of Lynch syndrome and this is the type of DNA alteration expected to cause the disorder. In summary, based on the above information, this variant meets our criteria to be classified as pathogenic. -

Jul 22, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 24474082, 25194673, 15949004, 12132870, 21868491, 26143115, 25107687, 15655560, 12362047, 15849733, 24344984, 23752102, 15235030, 21387278, 19419416, 27300758, 26666765, 27863258, 27601186, 27978560, 28127413, 28247034, 17473388, 17569143, 9739019, 28944238, 28874130, 29575718, 30274973, 30521064, 29025352, 31159747, 24969397, 31615790, 32338768, 30787465, 35861108, 36630951, 33804961, 32522261, 31830689, 34178123, 32549215, 24362816, 12624141, 31162827, 16451135, 33422027, 38344144) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH2: PVS1, PM2, PS4:Moderate -

Lynch syndrome 1 Pathogenic:5 Uncertain:1

Jul 29, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 07, 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. -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 23, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2022

Human Genetics Bochum, Ruhr University Bochum

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used to clasify this variant: PVS1, PM2, PS4 -

Jan 11, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4, PP5. -

Lynch syndrome Pathogenic:5

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 13 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome (PMID: 15849733, 16451135, 17312306, 17569143, 18289827, 19419416, 28874130, 29575718), as well as in individuals affected with pancreatic cancer (PMID: 30274973), colorectal cancer (PMID: 21868491, 30521064), or Muir-Torre syndrome (PMID: 15235030, 24474082). Tumor data from affected individuals has shown high microsatellite instability and/or loss of MSH2 protein via immunohistochemistry (PMID: 15235030, 17312306, 18289827, 24474082, 30521064). This variant has been identified in 1/31380 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

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 -

Jan 10, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MSH2 c.2131C>T (p.Arg711X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and others (e.g. c.2152C>T(p.Gln718X), c.2633_2634delA(p.Glu878fsX3), etc.). This variant is absent in 121400 control chromosomes from ExAC. In literature and clinical databases, this variant is reported as a pathogenic variant and is found in several HNPCC families/patients, including one patient with Muir-Torre Syndrome. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Jan 30, 2019

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 02, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Mar 29, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 13 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with pancreatic cancer (PMID: 30274973), colorectal cancer (PMID: 21868491, 30521064), Lynch syndrome (PMID: 15849733, 16451135, 17312306, 17569143, 18289827, 19419416, 28874130, 29575718), or Muir-Torre syndrome (PMID: 15235030, 24474082). This variant has been identified in 1/31380 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a point mutation replacing one nucleotide in the position 2131 of the MSH2 gene, leading in the replacement of Arginine with a termination stop codon in the position 711 of the MSH2 protein. This particular variant has been described in international literature in families with Lynch syndrome and with Muir-Torre syndrome (PMID: 17569143, PMID: 17473388, PMID: 16451135, PMID: 15235030). The mutation database ClinVar contains an entry for this variant (Variation ID: 90903). -

Jun 28, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R711* pathogenic mutation (also known as c.2131C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2131. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been detected in the germline of multiple patients with HNPCC/Lynch syndrome-associated malignancies and several of these individuals had tumors exhibiting a loss of MSH2 on immunohistochemistry (IHC) and/or microsatellite instability (Kurzawski G et al. J Med Genet, 2002 Oct;39:E65; Parc Y et al. J Med Genet, 2003 Mar;40:208-13; Mangold E et al. J. Med. Genet., 2004 Jul;41:567-72; Apessos A et al. Br J Cancer, 2005 Jan;92:396-404; Lagerstedt Robinson K et al. J Natl Cancer Inst, 2007 Feb;99:291-9; Papp J et al. World J Gastroenterol, 2007 May;13:2727-32; Tanyi M et al. Eur J Surg Oncol, 2008 Dec;34:1322-7; Tang R et al. Clin Genet, 2009 Apr;75:334-45; Rios CA et al. Sao Paulo Med J, 2014;132:61-4; Carneiro da Silva F et al. PLoS One, 2015 Oct;10:e0139753; Nowak JA et al. J Mol Diagn, 2017 01;19:84-91; DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Bannon SA et al. Cancer Prev Res (Phila), 2018 11;11:679-686; Ponz de Leon M et al. Scand J Gastroenterol, 2018 Jan;53:31-37; Schneider NB et al. Cancer Med, 2018 05;7:2078-2088; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Georgeson P et al. Mol Genet Genomic Med, 2019 07;7:e00781; Velázquez C et al. J Transl Med, 2020 06;18:232; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199; Xu Y et al. BMC Cancer, 2021 Jan;21:45). 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. -

not specified Pathogenic:1

Apr 30, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.2131C>T; p.Arg711Ter variant (rs63750636) is reported in several individuals with Lynch syndrome and an individual with Muir-Torre syndrome (Rios 2014, Rossi 2017, Schneider 2018, see LOVD InSiGHT link). This variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 90903). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to InSiGHT database: https://databases.lovd.nl/shared/variants/MSH2#object_id=VariantOnTranscript%2CVariantOnGenome&id=MSH2&order=VariantOnTranscript%2FDNA%2CASC&search_transcriptid=00013950&search_VariantOnTranscript/DNA=c.2131C%3ET&page_size=100&page=1 Rios CA et al. Muir-Torre syndrome: case report and molecular characterization. Sao Paulo Med J. 2014;132(1):61-4. Rossi BM et al. A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. BMC Cancer. 2017 Sep 5;17(1):623. Schneider NB et al. Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome. Cancer Med. 2018 May;7(5):2078-2088. -

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

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Sep 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg711*) 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). This variant is present in population databases (rs63750636, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Muir-Torre syndrome and/or non-polyposis colorectal cancer (PMID: 12132870, 12362047, 15235030, 15849733, 16451135, 17473388, 17569143, 18289827). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. ClinVar contains an entry for this variant (Variation ID: 90903). For these reasons, this variant has been classified as Pathogenic. -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	51
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.96
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs63750636; hg19: chr2-47703631; COSMIC: COSV51877754; COSMIC: COSV51877754;