2-47429881-C-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.1216C>T(p.Arg406Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,788 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. R406R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:24
• Conservation: PhyloP100: 2.62

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 2-47429881-C-T is Pathogenic according to our data. Variant chr2-47429881-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1755.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47429881-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1216C>T	p.Arg406Ter	stop_gained	7/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1216C>T	p.Arg406Ter	stop_gained	7/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461788 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727198

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2021	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; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Leach 1993, Kuismanen 2000, Kurzawski 2002, Casey 2005, Lagerstedt Robinson 2007, Grindedal 2009, Pastrello 2011, De Lellis 2013, Bashyam 2014, Ponti 2016, Brennan 2017, Vargas-Parra 2017); Not observed in large population cohorts (Lek et al., 2016); 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: 10793088, 24278394, 11879922, 21239990, 15713769, 28577310, 28944238, 29025352, 20591884, 18841495, 17312306, 8261515, 27016151, 25420488, 26300997, 26850131, 15849733, 19760518, 28449805, 20223024, 24710284, 28874130, 29238914, 24969397, 28491141, 31615790) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Mar 19, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 13, 2015	- -

Lynch syndrome 1 Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 17, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 17, 2023	The pathogenic MSH2 family variant was detected in this specimen. This sequence change creates a premature translational stop signal (p.Arg406*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 10793088,24278394, 11879922, 21239990, 15713769, 28577310, 28944238, 29025352, 20591884, 18841495, 17312306, 8261515, 27016151, 25420488, 26300997, 26850131, 15849733, 19760518, 28449805, 20223024, 24710284, 28874130, 29238914, 24969397, 28491141, 31615790). ClinVar contains an entry for this variant (Variation ID: 1755). For these reasons, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic mutations in the MSH2 gene cause Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC), also known as Lynch Syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 24, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 25, 2022	The MSH2 c.1216C>T variant is classified as Pathogenic (PVS1, PS4, PM2, PP4, PP5) The MSH2 c.1216C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 406 (PVS1). The variant has been frequently reported in probands with a clinical presentation of colorectal cancer (PS4). This variant is absent from population databases (PM2). The clinical features of this case are highly specific for the MSH2 gene due to loss of expression of MSH2/MSH in IHC tumour staining (PP4). The variant has been reported in dbSNP (rs63751108) and in the HGMD database: CM930497. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 1755), including the InSiGHT group (PP5). -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Aug 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 12, 2017	- -

Lynch syndrome Pathogenic:3

Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation introducing a premature termination codon -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 05, 2017	The p.Arg406X variant in MSH2 has been reported in >15 individuals with MSH2-associated cancers and segregated with disease in at least 1 affected relative (Leach 1993, Liu 1994, Weber 1997, Dunlop 1997, Wahlberg 1999, Pistoriu 2000, Mangold 2005, Casey 2005, Kurzawski 2006, Spaepen 2006, Guillem 2007, Choi 2009, Grindedal 2009, van der Post 2010, and Ponti 2014). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 406, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH2 gene is an established disease mechanism in individuals with Lynch syndrome. In addition, this variant was classified as pathogenic on Sept 13, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107079.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon reports in literature and absence from controls. ACMG/AMP Criteria applied: PVS1; PS4; PM2. -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

Carcinoma of colon Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH2 p.Arg406X variant was identified in 8 of 2328 proband chromosomes (frequency: 0.003) from Polish, German, Belgian, Uruguayan, British and Canadian individuals or families with Lynch Syndrome (Sarroca 2005, Kurzawski 2006, Mangold 2005, Spaepen 2006, Taylor 2003, Choi 2009). The variant was also identified in dbSNP (ID: rs63751108) “With Pathogenic allele”, Clinvitae database (classification pathogenic), COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as pathogenic and reviewed by an expert panel, submitters: InSiGHT, Ambry Genetics, LabCorp, OMIM, and Mayo Clinic), and UMD (18x with a “causal” classification). The p.Arg406X variant leads to a premature stop codon at position 406, 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 disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	3DMed Clinical Laboratory Inc	May 31, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 18, 2022	The p.R406* pathogenic mutation (also known as c.1216C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1216. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation has been detected in multiple families meeting Amsterdam criteria. Tumor samples from two of these affected exhibited loss of the MSH2 protein by IHC (De Lellis L et al. PLoS ONE. 2013 Nov;8(11):e81194; Chong G et al. Hum. Mutat. 2009 Aug;30(8):E797-812; Casey G et al. JAMA. 2005 Feb;293(7):799-809). One study detected this mutation in three HNPCC families and noted that it was not observed in 180 healthy control individuals (Pastrello C et al. Genet. In Med. 2011 Feb;13(2):115-24). This mutation was also seen in an individual affected with urinary bladder cancer at age 58 in addition to colorectal cancer at ages 33 and 34; authors suggested that MSH2 mutations may confer a higher risk of urinary tract cancer (van der Post RS et al. J. Med. Genet. 2010 Jul;47(7);464-70). This mutation has been reported in an individual with gallbladder cancer (Cloyd JM et al. Gastrointest Cancer. 2018 Mar;49(1):93-96) and in individuals with soft tissue sarcoma and sebaceous adenoma (Latham A et al. J Clin Oncol. 2018 Oct;JCO1800283). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 07, 2021	This variant changes 1 nucleotide in exon 7 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Lynch syndrome (PMID: 8261515, 12362047, 15713769, 15849733, 19459153, 20223024, 20591884, 21239990, 21590452, 24278394, 24278394, 24710284, 27016151, 30376427). This variant has not been identified 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. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

This sequence change creates a premature translational stop signal (p.Arg406*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 8261515, 15713769, 20223024, 20591884, 24710284). ClinVar contains an entry for this variant (Variation ID: 1755). 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.81	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.99
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs63751108; hg19: chr2-47657020; COSMIC: COSV51881634;