2-47414368-C-T

Position:

• chr2-47414368-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.892C>T​(p.Gln298*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,546 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: not found (cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 7.59

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 (HGNC:):

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 2-47414368-C-T is Pathogenic according to our data. Variant chr2-47414368-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 91239.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47414368-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.892C>T	p.Gln298*	stop_gained	5/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.892C>T	p.Gln298*	stop_gained	5/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460546 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726580

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 18, 2023	The MSH2 c.892C>T variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) The MSH2 c.892C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 298 (PVS1). The variant has been reported in individuals with a clinical presentation of Lynch syndrome-related cancers such as colorectal cancer (PMID: 25117503, 17312306, 34680242) and endometrial cancer (PMID: 24323032) (PS4_Mod). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs63750934) and in the HGMD database: CM011418. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 91239). -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 28, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 30, 2022	This variant changes 1 nucleotide in exon 5 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-associated cancers (PMID: 12658575, 31162827, 33977078), breast cancer (PMID: 20215533), endometrial cancer (PMID: 24323032, 26659639), prostate cancer (PMID: 25117503, 27013479, 28790115), and glioblastoma (PMID: 25648859). This variant has been reported in individuals affected with breast, endometrial, and prostate cancer that have demonstrated loss of MSH2 and MSH6 proteins by immunohistochemistry analyses (PMID: 20215533, 24323032, 27013479, 28790115). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 23, 2024	The p.Q298* pathogenic mutation (also known as c.892C>T), located in coding exon 5 of the MSH2 gene, results from a C to T substitution at nucleotide position 892. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This mutation has been identified in multiple families meeting Amsterdam criteria and/or with early onset Lynch-associated cancers (Wahlberg S et al, 1999;3:259-64; Wagner A et al. Am J Hum Genet, 2003 May;72:1088-100; Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83; Walsh MD et al. Clin Cancer Res, 2010 Apr;16:2214-24; Stojcev Z et al. Acta Biochim Pol, 2013 Jun;60:195-8; Buchanan DD et al. J. Clin. Oncol., 2014 Jan;32:90-100; Therkildsen C et al. Eur. J. Neurol., 2015 Apr;22:717-24; Tzortzatos G et al. Gynecol Oncol, 2015 Sep;138:717-22; Whitworth J et al. JAMA Oncol, 2016 Mar;2:373-9; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Georgeson P et al. Mol Genet Genomic Med, 2019 07;7:e00781). This mutation has also been detected in multiple individuals with prostate cancer whose tumors exhibited absent MSH2 and MSH6 via immunohistochemisty (Rosty C et al. Fam. Cancer, 2014 Dec;13:573-82; Dominguez-Valentin M et al. BMC Urol, 2016 Mar;16:15). 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. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH2 p.Gln298X variant was identified in 8 of 3362 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome associated cancers, endometrial cancer, prostate cancer, and glioblastoma (Dominguez-Valentin 2016, Therkildsen 2015, Buchanan 2014, Walsh 2010, Lagerstedt Robinson 2007, Wagner 2003, Wahlberg 1999); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in the following databases: dbSNP (ID: rs63750934) as "With Pathogenic allele", ClinVar (3x pathogenic), Clinvitae (3x pathogenic), Insight Colon Cancer Gene Variant Database (11x, pathogenic), Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (17x pathogenic). The variant was not identified in Cosmic, MutDB, UMD-LSDB, or the Zhejiang Colon Cancer Database. The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.892C>T variant leads to a premature stop codon at position 298 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 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. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Coding sequence variation resulting in a stop codon -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 26, 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; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene and other cancers in published literature (Wahlberg 1999, Buchanan 2014, Rosty 2014, Therkildsen 2015, Whitworth 2016, Lagerstedt-Robinson 2016).; This variant is associated with the following publications: (PMID: 20215533, 26177554, 26659639, 25648859, 27013479, 24323032, 10495924, 25525159, 25117503, 28528517, 27601186, 22949379, 28790115) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 23, 2021

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91239). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln298*) 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). -

Sigmoid colon cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

3DMed Clinical Laboratory Inc

Dec 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.94
GERP RS		5.1

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: rs63750934; hg19: chr2-47641507; COSMIC: COSV51885181; COSMIC: COSV51885181;